Alkyl-containing 5-acylindolinones, the preparation thereof and their use as medicaments

ABSTRACT

The present invention relates to alkyl-containing 5-acylindolinones of general formula  
                 
 
wherein R 1  to R 3  are defined herein, the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on protein kinases, particularly an inhibiting effect on the activity of glycogen synthase kinase (GSK-3).

RELATED APPLICATIONS

This application claims priority benefit under 35 USC 119(e) from U.S. Provisional Application 60/559,471 filed Apr. 5, 2004, which claims benefit from German Application DE 10 2004 012 068.4, filed Mar. 12, 2004.

DESCRIPTION OF THE INVENTION

The present invention relates to new alkyl-containing 5-acylindolinones of general formula

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable pharmacological properties, for example an inhibiting effect on protein kinases, particularly an inhibiting effect on the activity of glycogen-synthase-kinase (GSK-3), the preparation thereof, the use thereof for the prevention or treatment of diseases or conditions associated with an altered GSK-3 activity, particularly type I and type II diabetes mellitus, diabetes associated disorders such as diabetic neuropathy, degenerative neurological diseases such as Alzheimer's disease, stroke, neurotraumatic injuries, bipolar disorders, pharmaceutical compositions containing a compound of general formula (I) or a physiologically acceptable salt thereof and processes for the preparation thereof.

In the above formula I

-   R¹ denotes a straight-chain or branched C₁₋₅-alkyl group wherein the     hydrogen atoms may be wholly or partly replaced by fluorine atoms,     or -   an aryl group optionally substituted by a fluorine, chlorine or     bromine atom,     -   while by an aryl group is meant a phenyl or naphthyl group, -   R² denotes a C₁₋₇-alkyl or C₃₋₇-cycloalkyl group, -   a 5- or 6-membered heteroaryl group with one to three heteroatoms     selected from the group N, S and O, while both the heteratoms and     the substituents may be identical or different, optionally     substituted by one or two fluorine, chlorine, bromine or iodine     atoms or one or two nitro, cyano, amino, C₁₋₃-alkyl or C₁₋₃-alkoxy     groups, -   a phenyl group wherein two adjacent carbon atoms are linked together     through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy     group, -   a phenyl group, to which is anellated another phenyl ring or a 5- or     6-membered heteroaromatic ring with one to three heteroatoms     selected from the group N, S and O, while the heteratoms may be     identical or different, and the bicyclic group may be substituted by     one or two fluorine, chlorine, bromine or iodine atoms or one or two     nitro, cyano, amino, C₁₋₃-alkyl or C₁₋₃-alkoxy groups and the     substituents may be identical or different, or -   a phenyl group which may be substituted by one to three fluorine,     chlorine, bromine or iodine atoms or by one to three C₁₋₃-alkyl,     nitro, cyano, amino, di-(C₁₋₃-alkyl)-amino,     C₁₋₃-alkyl-carbonylamino, phenylcarbonylamino,     C₁₋₃-alkylsulphonylamino, arylsulphonylamino, trifluoromethyl,     C₁₋₃alkylsulphonyl, carboxy, C₁₋₃-alkoxy,     di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, C₁₋₃-alkoxy-carbonyl,     C₁₋₃-alkylaminocarbonyl, hydroxy-carbonyl-C₁₋₃-alkyl-aminocarbonyl,     C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl-aminocarbonyl,     di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-amino-carbonyl-C₁₋₃-alkoxy,     C₁₋₃-alkyl-amino-carbonyl-C₁₋₃-alkoxy, carboxy-C₁₋₃-alkoxy,     C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkoxy, carboxy-C₁₋₃-alkyl,     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl,     C₁₋₃-alkoxy-carbonyl-amino-C₁₋₃-alkyl, amino-C₁₋₃-alkyl,     di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl,     C₁₋₃-alkyl-carbonyl-amino-C₁₋₃-alkyl, phthalimido, pyrrolyl or mono-     or di-(C₁₋₃-alkyl)-pyrrolyl groups, while the substituents are     identical or different, and -   R³ denotes a hydrogen atom, -   a straight-chain or branched C₁₋₆-alkyl group which may be     substituted by one to three carboxy, C₁₋₄-alkoxy-carbonyl,     aminocarbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl,     di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-amino-carbonyl,     N-[di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)]-N-(C₁₋₃-alkyl)-amino-carbonyl,     arylaminocarbonyl, heteroarylaminocarbonyl,     aryl-C₁₋₃-alkyl-aminocarbonyl, heteroaryl-C₁₋₃-alkyl-aminocarbonyl,     N-(aryl)-N-(C₁₋₃-alkyl)-aminocarbonyl,     N-(heteroaryl)-N-(C₁₋₃-alkyl)-aminocarbonyl,     di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl, aryl or heteroaryl groups     or by a 5 to 7-membered cycloalkyleneimino or     cycloalkyleneiminocarbonyl group,     -   while in the above-mentioned cycloalkyleneimino or         cycloalkyleneimino-carbonyl group a methylene group may be         replaced in position 3 or 4 by an —NH—, —N(C₁₋₃-alkyl)- or         —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom         and/or in position 2, 3 or 4 by a carbonyl group, -   a straight-chain or branched C₂₋₆-alkyl group which is substituted     from position 2 onwards by one to three hydroxy, C₁₋₃-alkoxy,     aryloxy, heteroaryloxy, amino-C₁₋₃-alkyloxy,     C₁₋₃-alkyl-amino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy,     ω-hydroxy-C₂₋₃-alkoxy, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino,     heteroaryl-carbonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino,     N—(C₁₋₃-alkyl)-N-(heteroaryl-carbonyl)-amino,     C₁₋₄-alkoxy-carbonylamino,     N—(C₁₋₃-alkyl)-N-(C₁₋₄-alkoxy-carbonyl)-amino, arylcarbonylamino,     N-(C₁₋₃-alkyl)-N-(aryl-carbonyl)-amino,     (ω-hydroxy-C₂₋₃-alkyl)-amino, di-(ω-hydroxy-C₂₋₃-alkyl)-amino,     arylamino, heteroarylamino, C₁₋₃-alkylsulphonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino,     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino,     (C₁₋₃-alkyl-amino)-carbonyl-amino,     [di-(C₁₋₃-alkyl)-amino]-carbonyl-amino,     (C₁₋₃-alkyl-amino)-C₁₋₃-alkyl-carbonyl-amino,     [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyl-carbonyl-amino,     N-(aryl-C₁₋₁₃-alkyl-carbonyl)-N-(C₁₋₃-alkyl)-amino,     N-(C₁₋₃-alkyl)-N-[(C₁₋₃-alkyl-amino)-carbonyl]-amino or     N-(C₁₋₃-alkyl)-N-{[di-(C₁₋₃-alkyl)-amino]-carbonyl}-amino group and     may optionally additionally be substituted from position 1 onwards     by a carboxy, C₁₋₄-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl, arylamino-carbonyl,     heteroarylaminocarbonyl-, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl-,     aryl or heteroaryl group or by a 5 to 7-membered cycloalkyleneimino     or cycloalkyleneimino-carbonyl group,     -   while in the above-mentioned cycloalkyleneimino or         cycloalkyleneimino-carbonyl group a methylene group in position         3 or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or         —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom         and/or in position 2, 3 or 4 by a carbonyl group, -   a C₂₋₄-alkenyl or C₂₋₄-alkynyl group, while between the nitrogen     atom to which R³ is bound and the multiple bond there is at least     one sp³-hybridised carbon atom and the alkenyl or alkynyl group may     be substituted by one to three C₁₋₃-alkyl groups, -   a C₁₋₅-alkyl group in the methylene group which is adjacent to the     nitrogen atom to which R³ is bound may be replaced by an —NH—, or a     —N(C₁₋₃-alkyl)-group or by an oxygen atom, -   a C₁₋₄-alkyloxy group or -   an amino group which may be substituted by one or two C₁₋₃-alkyl,     aryl, aryl-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₄-alkyloxy-carbonyl,     arylcarbonyl or aryl-C₁₋₃-alkyl-carbonyl groups, while the     substituents may be identical or different, -   while the above-mentioned alkyl groups may be straight-chain or     branched, -   the tautomers, enantiomers, diastereomers, the mixtures thereof and     the salts thereof.

Unless otherwise stated, by a heteroaryl group or a heteroaromatic ring is preferably meant a furanyl, thiophenyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl group, which may be mono-, di- or trisubstituted by a fluorine, chlorine, bromine or iodine atom or an amino, nitro, cyano, C₁₋₃-alkyl, C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, or trifluoromethyl group, while the substituents are identical or different, and to which a phenyl ring may be fused via two adjacent atoms.

By an aryl group is meant, unless otherwise stated, a phenyl or naphthyl group; the phenyl group is preferred. Unless otherwise stated, an aryl group of this kind may be substituted by a nitro, cyano, C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyl, C₁₋₃-alkyl-amino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group.

Preferred are those compounds of general formula I, wherein

-   R² and R³ are as hereinbefore defined and -   R¹ denotes a methyl, ethyl, n-propyl, isopropyl, n-pentyl,     trifluoromethyl or phenyl group, -   the tautomers, enantiomers, diastereomers, the mixtures thereof and     the salts thereof.

Particularly preferred are those compounds of general formula I, wherein

-   R¹ denotes a methyl or ethyl group, -   R² denotes an ethyl, propyl, butyl or pentyl group, -   a pyridinyl, furanyl or pyrazinyl group, -   a phenyl group wherein two adjacent carbon atoms are linked together     through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy     group, or -   a phenyl group which may be substituted by one or two fluorine,     chlorine, bromine or iodine atoms or by one or two C₁₋₃-alkyl,     nitro, cyano, amino, C₁₋₃-alkylcarbonylamino, phenylcarbonylamino,     C₁₋₃-alkylsulphonylamino, trifluoromethyl, carboxy, C₁₋₃-alkoxy,     di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, C₁₋₃-alkoxy-carbonyl,     C₁₋₃-alkylaminocarbonyl, hydroxycarbonyl-C₁₋₃-alkyl-aminocarbonyl,     C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl-aminocarbonyl,     di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkylaminocarbonyl, carboxy-C₁₋₃-alkyl,     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl, amino-C₁₋₃-alkyl or     C₁₋₃-alkyl-carbonylamino-C₁₋₃-alkyl groups, while the substituents     are identical or different, and -   R³ denotes a hydrogen atom, -   a straight-chain or branched C₁₋₆-alkyl group which may be     substituted by a carboxy, C₁₋₄-alkoxy-carbonyl, phenyl, pyridinyl,     indolyl, imidazolyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl,     pyridinylaminocarbonyl, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl or     by a 5 to 7-membered cycloalkyleneimino or     cycloalkyleneiminocarbonyl group,     -   while the above-mentioned phenyl group may optionally be         substituted by nitro, cyano, C₁₋₃-alkyloxy,         [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyloxy, an amino-C₁₋₃-alkyl or         C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group and     -   in the above-mentioned cycloalkyleneimino and         cycloalkyleneiminocarbonyl group a methylene group in position 3         or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or         —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom         and/or in position 2, 3 or 4 by a carbonyl group, -   a straight-chain or branched C₂₋₆-alkyl group which is substituted     from position 2 onwards by a hydroxy, C₁₋₃-alkoxy,     ω-hydroxy-C₂₋₃-alkoxy, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino,     C₁₋₄-alkoxy-carbonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₄-alkoxy-carbonyl)-amino, phenylcarbonylamino,     N-(C₁₋₃-alkyl)-N-(phenylcarbonyl)-amino,     di-(ω-hydroxy-C₂₋₃-alkyl)-amino, pyridinylamino,     nitro-pyridinyl-amino, chloro-trifluoromethyl-pyridinylamino,     C₁₋₃-alkylsulphonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino or     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino group and may     optionally additionally be substituted from position 1 onwards by a     carboxy, C₁₋₄-alkoxy-carbonyl, phenyl, pyridinyl, imidazolyl,     C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     phenylaminocarbonyl, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl or by a     5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl     group,     -   while in the above-mentioned cycloalkyleneimino or         cycloalkyleneimino-carbonyl group a methylene group in position         3 or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or         —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom         and/or in position 2, 3 or 4 may be replaced by a carbonyl         group,     -   and the above-mentioned phenyl groups may optionally be         substituted by an amino-C₁₋₃-alkyl or         C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group, or -   or represent a propenyl or propynyl group, -   but particularly those compounds wherein -   R¹ denotes a methyl group, -   R² denotes an ethyl, propyl, butyl or pentyl group, -   a phenyl group wherein two adjacent carbon atoms are linked together     through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy     group, or -   a phenyl group which may be substituted by one or two fluorine,     chlorine or bromine atoms or by one or two trifluoromethyl, nitro,     cyano, C₁₋₃-alkoxy, carboxy-C₁₋₃-alkyl,     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl, amino-C₁₋₃-alkyl or     C₁₋₃-alkyl-carbonylamino-C₁₋₃-alkyl-groups, while the substituents     are identical or different, and -   R³ denotes a straight-chain or branched C₁₋₅-alkyl group which may     be substituted by a carboxy, C₁₋₄-alkoxy-carbonyl,     C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl,     phenylaminocarbonyl, pyridinylaminocarbonyl,     di-(2-hydroxy-ethyl)-aminocarbonyl, piperazinylcarbonyl,     4-(C₁₋₃-alkyl)-piperazinyl-carbonyl,     4-(C₁₋₄-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or     imidazolyl group,     -   while the phenyl group may optionally be substituted by a nitro,         cyano, C₁₋₃-alkyloxy, [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyloxy,         amino-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group, -   a C₂₋₅-alkyl group which is terminally substituted by a hydroxy,     C₁₋₃-alkoxy, phenyloxy, 2-hydroxy-ethoxy, amino, C₁₋₃-alkylamino,     di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino,     C₁₋₄-alkoxy-carbonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkoxy-carbonyl)-amino, phenylcarbonylamino,     N-(C₁₋₃-alkyl)—N-(phenylcarbonyl)-amino, pyridinylamino,     nitro-pyridinyl-amino, di-(2-hydroxy-ethyl)-amino,     3-chloro-5-trifluoromethyl-pyridin-2-yl-amino,     C₁₋₃-alkylsulphonylamino,     N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino,     C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino, indolyl,     pyrrolidinyl, 2-oxo-pyrrolidinyl, morpholinyl, piperazinyl or     4-(C₁₋₃-alkyl)-piperazinyl group and may optionally additionally be     substituted from position 1 onwards by a carboxy,     C₁₋₄-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl,     di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl,     di-(2-hydroxy-ethyl)-amino-carbonyl, piperazinylcarbonyl,     4-(C₁₋₃-alkyl)-piperazinyl-carbonyl,     4-(C₁₋₄-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or     imidazolyl group, or -   an amino group which may be substituted by one or two C₁₋₃-alkyl,     aryl, aryl-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₄-alkyloxy-carbonyl,     arylcarbonyl or aryl-C₁₋₃-alkyl-carbonyl groups, while the     substituents may be identical or different, -   while the above-mentioned alkyl groups may be straight-chain or     branched, -   the tautomers, enantiomers, diastereomers, the mixtures thereof and     the salts thereof.

Most particularly preferred are those compounds of general formula I, wherein

-   R¹ denotes a methyl group, -   R² denotes an ethyl, propyl, butyl or pentyl group, -   a phenyl group wherein two adjacent carbon atoms are linked together     through a methylenedioxy or ethylenedioxy group, or -   a phenyl group and -   R³ denotes a C₁₋₄-alkyl group which may be terminally substituted by     a C₁₋₄-alkoxy-carbonyl group, or -   a C₂₋₄-alkyl group which is terminally substituted by a     C₁₋₃-alkyl-carbonylamino, phenylcarbonylamino,     di-(C₁₋₃-alkyl)-amino, phenyl, pyridinyl or C₁₋₃-alkylsulphonylamino     group, -   while the above-mentioned alkyl groups may be straight-chain or     branched, -   the tautomers, enantiomers, diastereomers, the mixtures thereof and     the salts thereof; -   the following compounds of general formula I deserve particular     mention: -   (a)     5-acetyl-3-[3-(methoxycarbonylpropylamino)-(benzo-[1,3]dioxol-5-yl)-methylidene]-2-indolinone -   (b) 5-acetyl-3-[isopropylamino-phenyl-methylidene]-2-indolinone -   (c) 5-acetyl-3-[propylamino-phenyl-methylidene]-2-indolinone -   (d)     5-acetyl-3-[(3-methoxycarbonyl-propylamino)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methylidene]-2-indolinone -   (e)     5-acetyl-3-[(benzo[1,3]dioxol-5-yl)-(3-(benzoylamino-propylamino)-methylidene]-2-indolinone -   (f)     5-acetyl-3-[(benzo[1,3]dioxol-5-yl)-(3-(butyrylamino-propylamino)-methylidene]-2-indolinone -   (g)     5-acetyl-3-[(3-methanesulphonylamino-propylamino)-phenyl-methylidene]-2-indolinone -   (h)     5-acetyl-3-[1-(3,4-difluorophenyl)-1-(N′,N′-dimethylhydrazino)-methylidene]-2-indolinone -   (i) 5-acetyl-3-[1-(4-dimethylamino-butyl)-butenylidene]-2-indolinone -   (i)     5-acetyl-3-[1-phenyl-1-(3-pyridin-3-yl-propylamino)-methylidene]-2-indolinone     as well as the tautomers, enantiomers, diastereomers, the mixtures     thereof and the salts thereof.

According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

-   a) reacting a compound of general formula     wherein R¹ and R² are as hereinbefore defined, -   R¹⁸ denotes a hydrogen atom or a protective group for the nitrogen     atom of the lactam group and -   Z denotes a leaving group such as e.g. a halogen atom, a hydroxy,     alkoxy, alkyl-sulphonyl, trialkylsilyloxy-, alkyl-arylsulphonyl, or     aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy,     ethoxy, methanesulphonyl, trimethylsilyloxy, toluene-sulphonyl or     benzyloxy group,     with an amine of general formula     R³—NH₂  (III),     wherein R³ is as hereinbefore defined,     while any hydroxy, amino or imino groups optionally contained in the     groups R² and/or R³ may be temporarily protected by suitable     protective groups.

A suitable protective group for the nitrogen atom of the lactam group may be for example an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group.

The reaction is expediently carried out in a solvent such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisopropylamine or sodium hydrogen carbonate, at temperatures between 20 and 175° C., while any protective group used may simultaneously be cleaved as a result of transamidation.

If Z in a compound of general formula II denotes a halogen atom, then the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120° C.

If Z in a compound of general formula II denotes a hydroxy, alkoxy or arylalkoxy group, then the reaction is preferably carried out at temperatures between 20 and 200° C.

If any protecting group used subsequently has to be cleaved, this is conveniently carried out either hydrolytically in an aqueous or alcoholic solvent, e.g. in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100° C., preferably at temperatures between 10 and 50° C.,

-   or advantageously by transamidation with an organic base such as     ammonia, butylamine, dimethylamine or piperidine in a solvent such     as methanol, ethanol, dimethylformamide and mixtures thereof or in     an excess of the amine used at temperatures between 0 and 100° C.,     preferably at temperatures between 10 and 50° C. -   b) in order to prepare a compound of formula I which contains an     aminocarbonyl group: -   reacting a compound which contains a carboxy group with the     corresponding amine to obtain the corresponding aminocarbonyl     compound; -   c) in order to prepare a compound of formula I which contains a     carbonylamino group: -   reacting a compound which contains an amino group with the     corresponding acid chloride to obtain the corresponding     carbonylamino compound; -   d) in order to prepare a compound of formula I which contains an     aminomethyl group: hydrogenating a compound which contains a cyano     group to obtain the corresponding aminomethyl derivative; -   e) in order to prepare a compound of formula I which contains an     amino group: -   reducing a compound which contains a nitro group.

Then any protective groups optionally used during the reaction may be cleaved and/or

-   the compounds of general formula I thus obtained may be resolved     into their enantiomers and/or diastereomers and/or -   the compounds of formula I obtained may be converted into the salts     thereof, particularly for pharmaceutical use into the     physiologically acceptable salts thereof with inorganic or organic     acids or bases.

Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (−)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (−)-menthyloxycarbonyl.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds of general formulae II to III used as starting materials are either known from the literature or may be obtained by methods known from the literature (cf. Examples I to VIII).

As already mentioned hereinbefore, the compounds according to the invention of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on the enzyme GSK-3.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which exists in two isoforms, GSK-3α and GSK-3β. GSK-3 phosphorylates and inactivates not only glycogen synthase, a key enzyme of the insulin-dependent regulation of glycogen synthesis (Embi et al., Eur. J. Biochem. 107, 519-527, (1980)), but also a number of other regulatory proteins in vitro. These proteins include the microtubule associated protein Tau, elongation initiation factor 2b (eIF2b), β-catenin, axin, ATP-citratelyase, heat-shock-factor 1, c-jun, c-myc, c-myb, CREB and CEBPα. These different substrates imply a role for GSK-3 in numerous fields of cell metabolism, proliferation, differentiation and development.

Type 2 diabetes is characterised by insulin resistance in various tissues such as skeletal muscle, liver and fatty tissue and by altered secretion of insulin from the pancreas. The storage of glycogen in liver and muscle is of great importance for maintaining the glucose equilibrium. In type 2 diabetes the activity of glycogen synthase is reduced and thus the rate of glycogen synthesis is reduced. It has also been shown that GSK-3 is expressed to a greater extent in type 2 diabetic muscle and hence a reduced GSK-3 activity is associated with a reduced rate of glycogen synthesis (Nikoulina et al., diabetes 49, 263-271, (2000)). Inhibition of the GSK-3 activity stimulates glycogen synthase, thus intensifies glycogen synthesis and leads eventually to a reduction in the glucose levels. GSK-3 inhibition is therefore of therapeutic relevance for the treatment of type 1 and type 2 diabetes and also diabetic neuropathy.

Alzheimer's disease is characterised in that the microtubule-associated protein Tau is present in excessively strongly phosphorylated form (Cohen & Frame, Nature Reviews: Molecular Cell Biology, 2, 1-8, (2001)). GSK-3 phosphorylates many of these phosphorylations sites of Tau in vitro, thereby preventing binding to microtubules. As a result, Tau is available for increased filament assembly, which is at the root of Alzheimer's disease and other neurological diseases of neuronal degeneration. It has been shown that GSK-3 inhibitors such as insulin or lithium bring about partial dephosphorylation of Tau in neuronal cells (Cross et al., J. Neurochem. 77, 94-102 (2001)). GSK-3 inhibition may therefore be of therapeutic relevance for the treatment of degenerative neurological diseases such as Alzheimer's disease.

Inhibitors of GSK-3 activity may thus be of therapeutical and/or preventive benefit for a number of diseases where it is useful to inhibit GSK-3, such as diabetes and diabetes-associated diseases, chronic neurodegenerative diseases and dementias, such as Alzheimer's disease, Parkinson's syndrome, Pick's disease, dementia in subcortical arteriosclerotic encephalopathy (SAE), Huntington's chorea, multiple sclerosis, infectious diseases (meningoencephalitis, syphilis, brain abscess, Creutzfeldt-Jakob disease, AIDS), dementia complex with Lewy bodies, neurotraumatic diseases such as acute stroke, schizophrenia, manic depression, brain haemorrhage, alopecia, obesity, atherosclerotic cardiovaskular diseases, high blood pressure, PCO syndrome, metabolic syndrome, ischaemia, cancer, leukopenia, Down's syndrome, inflammations, immunodeficiency.

A new study (Sato, N. et al., Nature Medicine 10, 55-63 (2004)) shows that GSK-3 inhibitors may acquire the pluripotence of stem cells, which may open up new possibilities in the field of regenerative therapies using stem cells.

Determining the GSK-3 Activity

The effect of substances on the GSK-3 activity was carried out according to the following test method, based on the phosphorylation of a 26mer peptide (YRRMVPPSPSLSRHSSFHQpSEDEEE) from glycogen synthase, the sequence of which contains the phosphorylation sites for GSK-3 and the prephosphorylation of which is indicated by (pS).

The test substance is dissolved in DMSO/water. GSK3β (University of Dundee, UK) dissolved in 10 mM MOPS (morpholinopropanesulphonic acid), 0.05 mM EDTA, 0.005% Brij, 2.5% glycerol, 0.05% mercaptoethanol, pH 7.0, is combined with 10 μM [³³P]-ATP, 0.25 μM of 26mer peptide and incubated with the dissolved substance in 50 mM tris, 10 mM MgCl₂, 0.1% mercaptoethanol, pH 7.5, at ambient temperature. The reaction was stopped by the addition of 75 mM phosphoric acid. The reaction mixture was transferred onto Phosphocellulose filter plates (Millipore) and filtered to dryness and washed twice with 75 mM phosphoric acid. The phosphorylation was determined by measuring the radioactivity on the filter in a scintillation counter (Topcount, Packard). The ability of a substance to inhibit GSK-3 is determined by comparing the signal of a reaction mixture containing various concentrations of the substance with the signal of the reaction mixture without any substance. The IC₅₀ values are calculated by non-linear regression analysis using GraphPad Prism software.

Typical IC₅₀ values for the substances investigated were between 0.0001 μM and 1 μM.

Determining Glycogen Synthesis

This test serves to investigate the effect of test substances on glycogen synthesis in cells.

C3A hepatoma cells (ATCC) are seeded at a density of 100000 cells/ml in 96-well plates and grown to confluence as a monolayer in the medium. The medium is removed and the cells are washed several times with PBS and then incubated in KRBH buffer (134 mM NaCl, 3.5 mM KCl, 1.2 mM KH₂PO₄, 0.5 mM MgSO₄, 1.5 mM CaCl₂, 5 mM NaHCO₃, 10 mM HEPES, pH 7.4) with 0.1% BSA and 0.5 mM glucose for 60 min at 37° C. Test substance and 0.2 μCi D-[U¹⁴C]glucose (Amersham) are added and the cells are incubated for a further 60 min under the same conditions. After the removal of the incubation buffer the cells are washed several times with cold PBS and then lysed for 10 min at 37° C. and 10 min at ambient temperature with 1 M NaOH. The cell lysates are transferred onto filter plates and the glycogen is precipitated by incubating for 2 h with cold ethanol (70%) on ice. The precipitates are washed several times with ethanol and filtered to dryness. The glycogen synthesised is determined by measuring the radioactivity (14C-glucose incorporated) on the filter plates in a scintillation counter (Topcount, Packard).

The ability of a substance to stimulate glycogen synthesis is determined by comparing the signal of a reaction mixture containing various concentrations of the substance with the signal of the reaction mixture without any substance.

Oral Glucose Tolerance Test

Fasted db/db mice 7 to 9 weeks old (Janvier, France) are weighed and blood is taken from the tip of the tail. This blood is used for the first measurement of glucose on the basis of which the animals are randomised and divided into groups. The test substance to be tested may be given either orally or i.p. as a suspension in 0.5% Natrosol. 30 minutes after the administration of the substance the animals are given orally 2 g/kg glucose in a volume of 0.1 ml/100 g body weight dissolved in NaCl solution. Subsequently, the glucose values are determined from the tail blood using a glucometer (Ultra OneTouch, Lifescan) at specific time intervals [30, 60, 120 and 180 minutes after oral administration of the glucose].

For example, compound 1.009 exhibits a significant activity in the oral glucose tolerance test.

The compounds prepared according to the invention are well tolerated as, for example, after oral administration of 10 mg/kg of the compound of Example 1.009 to mice no changes were observed in the animals' behaviour.

The compounds according to the invention may also be used in combination with other active substances. Therapeutic agents which are suitable for such a combination include, for example, antidiabetic agents such as metformin, sulphonylureas (e.g. glibenclamid, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinediones (e.g. rosiglitazone, pioglitazone), PPAR-gamma-agonists (e.g. GI 262570) and antagonists, PPAR-gamma/alpha modulators (e.g. KRP 297), alpha-glucosidase inhibitors (e.g. acarbose, voglibose), DPP-IV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (e.g. exendin-4) or amylin. The list also includes SGLT2-inhibitors such as T-1095, inhibitors of protein tyrosinephosphatase 1, substances that affect deregulated glucose production in the liver, such as e.g. inhibitors of glucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenol pyruvate carboxykinase, pyruvate dehydrokinase, lipid lowering agents such as for example HMG-CoA-reductase inhibitors (e.g. simvastatin, atorvastatin), fibrates (e.g. bezafibrate, fenofibrate), nicotinic acid and the derivatives thereof, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors (e.g. avasimibe) or cholesterol absorption inhibitors such as, for example, ezetimibe, bile acid-binding substances such as, for example, cholestyramine, inhibitors of ileac bile acid transport, HDL-raising compounds such as CETP inhibitors or ABC1 regulators or active substances for treating obesity, such as sibutramine or tetrahydrolipostatin, dexfenfluramine, axokine, antagonists of the cannabinoid1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or β3-agonists such as SB-418790 or AD-9677 and agonists of the 5HT2c receptor.

In addition, combinations with drugs for influencing high blood pressure such as e.g. A-II antagonists or ACE inhibitors, diuretics, β-blockers, Ca-antagonists and others or combinations thereof are suitable.

Generally speaking, GSK-3 inhibitors may be administered in various ways: by oral, transdermal, intranasal or parenteral route or, in special cases, by intrarectal route. The preferred method of administration is by oral route daily, possibly several times a day. GSK-3 inhibitors are effective over wide dosage range. Thus, the dosage may be between 0.001 and 100 mg/kg, for example.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

The Examples that follow are intended to illustrate the invention:

Preparation of the Starting Compounds:

EXAMPLE I 5-acetyl-2-indolinone

171 g (1.28 mol) aluminium chloride in 500 ml 1,2-dichloroethane are cooled in the ice bath. Then 78 g (1,1 mol) acetylchloride are added dropwise, so that the temperature does not exceed 10° C. After 1 h 71.3 g (0.53 mol) 2-indolinone (1,3-dihydro-indol-2-one) are added in 4 batches and the temperature is maintained at 10-12° C. The reaction mixture is left overnight to come up slowly to ambient temperature. Then the solution is slowly added to 1 kg ice with vigorous stirring. The slurry is diluted with 1 l water and stirred for another 30 min. Then the precipitate is suction filtered.

Yield: 80.9 g (86.3% of theory)

R_(f)=0.36 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)

C₁₀H₉NO₂ (MW=175.19)

Mass spectrum: m/z=174 (M−H)⁻

The following compounds are prepared analogously to Example I:

(1) 5-propiony1-2-indolinone

Prepared from 2-indolinone and propionyl chloride

Yield: 72% of theory

R_(f)=0.44 (silica gel, methylene chloride/methanol 9:1)

C₁₁H₁₁NO₂(MW=189.22)

Mass spectrum: m/z=188 (M−H)⁻

(2) 5-butyryl-2-indolinone

Prepared from 2-indolinone and butyric acid chloride (butyrylchloride)

Yield: 68% of theory

C₁₂H₁₃NO₂ (MW=203.24)

Mass spectrum: m/z=202 (M−H)⁻

(3) 5-isobutyryl-2-indolinone

Prepared from 2-indolinone and isobutyrylchloride

Yield: 13% of theory

C₁₂H₁₃NO₂ (MW=203.24)

Mass spectrum: m/z=202 (M−H)⁻

(4) 5-hexanoyl-2-indolinone

Prepared from 2-indolinone and hexanoic acid chloride

Yield: 88% of theory

R_(f)=0.51 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)

C₁₄H₁₇NO₂ (MW=231.30)

Mass spectrum: m/z=230 (M−H)⁻

(5) 5-benzoyl-2-indolinone

Prepared from 2-indolinone and benzoic acid chloride

Yield: 80% of theory

R_(f)=0.46 (silica gel, methylene chloride/methanol 9:1)

C₁₅H₁₁NO₂ (MW=237.26)

Mass spectrum: m/z=236 (M−H)⁻

EXAMPLE II 1,5-diacetyl-2-indolinone

48.9 g (0.279 mol) 5-acetyl-2-indolinone are stirred in 400 ml acetic anhydride in an oil bath at 140° C. for 2 h. The starting material dissolves during this time.

Then the reaction mixture is left to cool, evaporated down, the precipitate is removed by suction filtering, washed with ether and the product is dried.

Yield: 56.0 g (92.4% of theory)

R_(f)=0.41 (silica gel, methylene chloride/methanol 50:1)

C₁₂H₁₁NO₃ (MW=217.223)

Mass spectrum: m/z=216 (M−H)⁻

The following compounds are prepared analogously to Example II:

(1) 1-acetyl-5-propionyl-2-indolinone

Prepared from 5-propionyl-2-indolinone and acetic anhydride

Yield: 79% of theory

R_(f)=0,68 (silica gel, methylene chloride/methanol 9:1)

C₁₃H₁₃NO₃ (MW=231.25)

Mass spectrum: m/z=232 (M+H)⁺

(2) 1-acetyl-5-benzoyl-2-indolinone

Prepared from 5-benzoyl-2-indolinone and acetic anhydride

Yield: 89% of theory

R_(f)=0,60 (silica gel, methylene chloride/methanol 30:1)

C₁₇H₁₃NO₃ (MW=279.294)

Mass spectrum: m/z=278 (M−H)⁻

(3) 1-acetyl-5-hexanoyl-2-indolinone

Prepared from 5-hexanoyl-2-indolinone and acetic anhydride

R_(f)=0,74 (silica gel, methylene chloride/methanol 30:1)

C₁₆H₁₉NO₃ (MW=273.33)

Mass spectrum: m/z=272 (M−H)⁻

EXAMPLE III 1,5-diacetyl-3-(ethoxy-phenyl-methylidene)-2-indolinone

32.6 g (150 mmol) 1,5-diacetyl-2-indolinone are suspended in 100 ml triethyl orthobenzoate and stirred overnight at 110° C. with 150 ml acetic anhydride. Then another 50 ml triethyl orthobenzoate are added and the mixture is stirred for another 24 h. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.

Yield: 38 g (72.5% of theory)

R_(f)=0.60 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₉NO₄ (MW=349.384)

Mass spectrum: m/z=350 (M+H)⁺

The following compounds are prepared analogously to Example III:

(1) 1-acetyl-5-hexanoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 1-acetyl-5-hexanoyl-2-indolinone and triethyl orthobenzoate

Yield: 29% of theory

R_(f)=0,72 (silica gel, methylene chloride/methanol 30:1)

C₂₅H₂₇NO₄ (MW=405.491)

Mass spectrum: m/z=428 (M+Na)⁺

(2) 1-acetyl-5-benzoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 1-acetyl-5-benzoyl-2-indolinone and triethyl orthobenzoate

Yield: 65% of theory

R_(f)=0,72 (silica gel, methylene chloride/methanol 30:1)

C₂₆H₂₁NO₄ (MW=411.455)

Mass spectrum: m/z=412 (M+H)⁺

(3) 1,5-diacetyl-3-(1-methoxy-propylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthopropionate

Yield: 80% of theory

R_(f)=0.50 (silica gel, methylene chloride/methanol 50:1)

C₁₆H₁₇NO₄ (MW=287.311)

Mass spectrum: m/z=288 (M+H)⁺

(4) 1,5-diacetyl-3-(1-methoxy-butylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthobutyrate

Yield: 71% of theory

R_(f)=0.53 (silica gel, methylene chloride/methanol 50:1)

C₁₇H₁₉NO₄ (MW=301.337)

Mass spectrum: m/z=302 (M+H)⁺

(5) 1,5-diacetyl-3-(1-methoxy-pentylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and trimethyl orthovalerate

Yield: 66% of theory

R_(f)=0.60 (silica gel, methylene chloride/methanol 50:1)

C₁₈H₂₁NO₄ (MW=315.364)

Mass spectrum: m/z=316 (M+H)⁺

(6) 1,5-diacetyl-3-(1-methoxy-2-methyl-propylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 1,1,1-trimethoxy-2-methylpropane

Yield: 40% of theory

R_(f)=0.71 (silica gel, ethyl acetate:cyclohexane:methanol 9:9:2)

C₁₇H₁₉NO₄ (MW=301.337)

Mass spectrum: m/z=302 (M+H)⁺

(7) 1,acetyl-5-propionyl-3-(1-methoxy-propylidene)-2-indolinone

Prepared from 1-acetyl-5-propionyl-2-indolinone and trimethyl orthopropionate

(8) 1,acetyl-5-hexanonyl-3-(1-methoxy-propylidene)-2-indolinone

Prepared from 1-acetyl-5-hexanoyl-2-indolinone and trimethyl orthopropionate

EXAMPLE IV 1-acetyl-5-butyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone

10 g (49 mmol) 5-butyryl-2-indolinone (Ex. 1.2) are stirred in 200 ml acetic anhydride for 5 h at 130° C. Then 35 ml triethyl orthobenzoate are added and the mixture is stirred for a further 4 h at 100° C. Then it is evaporated down and the resulting precipitate is suction filtered, washed and dried.

Yield: 11.5 g (62% of theory)

R_(f)=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)

C₂₃H₂₃NO₄ (MW=377.438)

Mass spectrum: m/z=378 (M+H)⁺

The following compounds are prepared analogously to Example IV:

(1) 1-acetyl-5-isobutyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 5-isobutyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate

R_(f)=0.55 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2) (2) 1,5-diacetyl-3-[1-methoxy-ethylidene]-2-indolinone

Prepared from 5-acetyl-2-indolinone, acetic anhydride and trimethyl orthoacetate

R_(f)=0.40 (silica gel, methylene chloride/methanol 50:1) (3) 1-acetyl-5-propionyl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 5-propionyl-2-indolinone, acetic anhydride and triethyl orthobenzoate

R_(f)=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2) (4) 1-acetyl-5-hexanoyl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 5-hexanoyl-2-indolinone, acetic anhydride and triethyl orthobenzoate

R_(f)=0.72 (methylene chloride/methanol 30:1) (5) 1-acetyl-5-butyryl-3-(ethoxy-phenyl-methylidene)-2-indolinone

Prepared from 5-butyryl-2-indolinone, acetic anhydride and triethyl orthobenzoate

R_(f)=0.79 (silica gel, ethyl acetate/cyclohexane/methanol 9:9:2)

EXAMPLE V 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone

4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are stirred overnight together with 4 g 3,4-dimethoxybenzoic acid, 7.1 g TBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate) and 14 ml triethylamine in 80 ml DMF (dimethylformamide) at ambient temperature. Then the mixture is poured onto 300 ml ice water with 10 ml of conc. hydrochloric acid and the precipitate formed is suction filtered. The residue is washed with a little methanol and then with ether.

Yield: 6.2 g (81.3% of theory)

R_(f)=0.85 (silica gel, methylene chloride/methanol 9:1)

C₂₁H₁₉NO₆ (MW=381.382)

Mass spectrum: m/z=381 (M)⁺

The following compounds are prepared analogously to Example V: (1) 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and piperonylic acid (benzo[1,3]dioxole-5-carboxylic acid)

Yield: 60% of theory

R_(f)=0.70 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₁₅NO₆ (MW=365.339)

Mass spectrum: m/z=366 (M+H)⁺ (2) 1,5-diacetyl-3-[(4-nitro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-nitrobenzoic acid

Yield: 82% of theory

R_(f)=0.38 (silica gel, methylene chloride/methanol 9:1)

C₁₉H₁₄N₂O₆ (MW=366.328)

Mass spectrum: m/z=367 (M+H)⁺ (3) 1,5-diacetyl-3-[(3-nitro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3-nitrobenzoic acid

Yield: 75% of theory

R_(f)=0.38 (silica gel, methylene chloride/methanol 9:1)

C₁₉H₁₄N₂O₆ (MW=366.328)

Mass spectrum: m/z=367 (M+H)⁺ (4) 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and monomethyl terephthalate

Yield: 71% of theory

R_(f)=0.41 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₇NO₆ (MW=379.366)

Mass spectrum: m/z=380 (M+H)⁺ (5) 1,5-diacetyl-3-[(4-chloro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-chlorobenzoic acid

Yield: 87% of theory

C₁₉H₁₄ClNO₄ (MW=355.776)

Mass spectrum: m/z=356/358 (M+H)⁺ (6) 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3,4-dichlorobenzoic acid

Yield: 83% of theory

C₁₉H₁₃Cl₂NO₄ (MW=390.221)

Mass spectrum: m/z=390/392/394 (M+H)⁺ (7) 1,5-diacetyl-3-[(4-cyano-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-cyanobenzoic acid

Yield: 71% of theory

R_(f)=0.32 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₁₄N₂O₄ (MW=346.341)

Mass spectrum: m/z=347 (M+H)⁺ (8) 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-trifluoromethyl-benzoic acid

Yield: 83% of theory

C₂₀H₁₄F₃NO₄ (MW=389.328)

Mass spectrum: m/z=390 (M+H)⁺ (9) 1,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 2,3-dihydro-1.4-benzodioxine-6-carboxylic acid

Yield: 90% of theory

R_(f)=0.75 (silica gel, methylene chloride/methanol 9:1)

C₂₁H₁₇NO₆ (MW=379.366)

Mass spectrum: m/z=380 (M+H)⁺ (10) 1,5-diacetyl-3-[(3-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3-methoxybenzoic acid

Yield: 70% of theory

R_(f)=0.67 (silica gel, methylene chloride/methanol 9:1) (11) 1,5-diacetyl-3-[(4-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-methoxybenzoic acid

Yield: 59% of theory

R_(f)=0.39 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₁₇NO₅ (MW=351.356)

Mass spectrum: m/z=350 (M−H)⁻ (12) 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1-acetyl-5-propionyl-2-indolinone and piperonylic acid (benzo[1,3]-dioxole-5-carboxylic acid)

Yield: 67% of theory

R_(f)=0.49 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₇NO₆ (MW=379.366)

Mass spectrum: m/z=380 (M+H)⁺ (13) 1,5-diacetyl-3-[(4-bromophenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-bromobenzoic acid

Yield: 89% of theory

C₁₉H₁₄BrNO₄ (MW=400.227)

Mass spectrum: m/z=400/402 (M+H)⁺ (14) 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3,5-dichlorobenzoic acid

Yield: 79% of theory

R_(f)=0.26 (silica gel, methylene chloride/methanol 30:1)

C₁₉H₁₃Cl₂NO₄ (MW=390.221)

Mass spectrum: m/z=390/392/394 (M+H)⁺ (15) 1,5-diacetyl-3-[(3,5-dimethoxyphenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3,5-dimethoxybenzoic acid

Yield: 83% of theory

R_(f)=0.37 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₉NO₆ (MW=381.382)

Mass spectrum: m/z=382 (M+H)⁺ (16) 1,5-diacetyl-3-[(2-chloro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 2-chlorobenzoic acid

Yield: 96% of theory

C₁₉H₁₄ClNO₄ (MW=355.776)

Mass spectrum: m/z=356/358 (M+H)⁺ (17) 1,5-diacetyl-3-[(2-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 2-methoxybenzoic acid

Yield: 27% of theory

C₂₀H₁₇NO₅ (MW=351.356)

Mass spectrum: m/z=352 (M+H)⁺ (18) 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 2,6-difluorobenzoic acid

Yield: 52% of theory

C₁₉H₁₃F₂NO₄ (MW=357.311)

Mass spectrum: m/z=358 (M+H)⁺ (19) 1,5-diacetyl-3-[(4-fluorophenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-fluorobenzoic acid

Yield: 77% of theory C₁₉H₁₄FNO₄ (MW=339.321)

Mass spectrum: m/z=338 (M−H)⁻ (20) 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3,4-difluorobenzoic acid

Yield: 91% of theory (21) 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 2,2-difluoro-benzo[1,3]dioxol-5-carboxylic acid

Yield: 69% of theory

C₂₀H₁₃F₂NO₆ (MW=401.32)

Mass spectrum: m/z=402 (M+H)⁺ (22) 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-(2-methoxycarbonyl-ethyl)-benzoic acid

Yield: 23% of theory

C₂₃H₂₁NO₆ (MW=407.42)

Mass spectrum: m/z=408 (M+H)⁺ (23) 1,5-diacetyl-3-[(pyrazin-2-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and pyrazine-2-carboxylic acid

Yield: 57% of theory

C₁₇H₁₃N₃O₄ (MW=323.311)

Mass spectrum: m/z=324 (M+H)⁺ (24) 1,5-diacetyl-3-[(pyridin-4-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and isonicotinic acid (pyridine-4-carboxylic acid)

Yield: 87% of theory

C₁₈H₁₄N₂O₄ (MW=322.323)

Mass spectrum: m/z=323 (M+H)⁺ (25) 1,5-diacetyl-3-[(furan-3-yl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and furan-3-carboxylic acid

Yield: 73% of theory

C₁₇H₁₃NO₅ (MW=311.297)

Mass spectrum: m/z=312 (M+H)⁺ (26) 1,5-diacetyl-3-[(4-diethylaminomethyl-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-diethylaminomethyl-benzoic acid

Yield: 10% of theory

C₂₄H₂₆N₂O₄ (MW=406.486)

Mass spectrum: m/z=407 (M+H)⁺ (27) 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-methoxycarbonyl-methoxy-benzoic acid

Yield: 43% of theory

C₂₂H₁₉NO₇ (MW=409.39)

Mass spectrum: m/z=410 (M+H)⁺ (28) 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-methylsulphonyl-benzoic acid

Yield: 25% of theory

C₂₀H₁₇NO₆S (MW=399.418)

Mass spectrum: m/z=400 (M+H)⁺ (29) 1,5-diacetyl-3-[(4-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 4-diethylamino-ethoxy-benzoic acid

Yield: 27% of theory

C₂₅H₂₈N₂O₅ (MW=436.500)

Mass spectrum: m/z=437 (M+H)⁺ (30) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid

Yield: 43% of theory

C₂₅H₂₈N₂O₅ (MW=436.500)

Mass spectrum: m/z=437 (M+H)⁺ (31) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid

Yield: 43% of theory

C₂₅H₂₈N₂O₅ (MW=436.500)

Mass spectrum: m/z=437 (M+H)⁺ (31) 1,5-diacetyl-3-[(3-(2-diethylamino-ethoxy)-phenyl)-hydroxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and 3-diethylamino-ethoxy-benzoic acid

Yield: 43% of theory

C₂₅H₂₈N₂O₅ (MW=436.500)

Mass spectrum: m/z=437 (M+H)⁺ (32) 1,5-diacetyl-3-(1-hydroxy-heptylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and heptanoic acid (33) 1,5-diacetyl-3-(1-hydroxy-hexylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and hexanoic acid (34) 1,5-diacetyl-3-(1-hydroxy-3-methyl-butylidene)-2-indolinone

Prepared from 1,5-diacetyl-2-indolinone and isovaleric acid

EXAMPLE VI 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-methoxy-methylidene]-2-indolinone

4.0 g (10.5 mmol) 1,5-diacetyl-3-[(3,4-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V) are suspended in 100 ml methylene chloride and combined with 3.1 g (21 mmol) trimethyloxonium tetrafluoroborate and 7.2 ml Hünig base (ethyldiisopropylamine) at ambient temperature. The solution is stirred for 3 h, then another 1.55 g trimethyloxonium tetrafluoroborate and 3.5 ml Hünig base are added and the mixture is stirred overnight. After the same amount of reagent has been added again and the mixture has been stirred for a further 5 h, the reaction is washed three times with water, the organic phase is dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 9:1, the corresponding fractions are combined and concentrated by rotary evaporation.

Yield: 1.6 g (37% of theory)

R_(f)=0.78 (silica gel, methylene chloride/methanol 50:1)

C₂₂H₂₁NO₆ (MW=395.409)

Mass spectrum: m/z=396 (M+H)⁺

The following compounds are prepared analogously to Example VI: (1) 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.1)

Yield: 85% of theory

R_(f)=0.55 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₇NO₆ (MW=379.366)

Mass spectrum: m/z=380 (M+H)⁺ (2) 1,5-diacetyl-3-[(4-nitro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-nitro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.2)

Yield: 82% of theory

R_(f)=0.55 (silica gel, methylene chloride/methanol 30:1)

C₂₀H₁₆N₂O₆ (MW=380.354)

Mass spectrum: m/z=381 (M+H)⁺ (3) 1,5-diacetyl-3-[(3-nitro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3-nitro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.3)

Yield: 43% of theory

R_(f)=0.44 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₁₆N₂O₆ (MW=380.354)

Mass spectrum: m/z=381 (M+H)⁺ (4) 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-methyloxycarbonyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.4)

Yield: 52% of theory

R_(f)=0.56 (silica gel, methylene chloride/methanol 30:1)

C₂₂H₁₉NO₆ (MW=393.393)

Mass spectrum: m/z=394 (M+H)⁺ (5) 1,5-diacetyl-3-[(4-chloro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-chloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.5)

Yield: 65% of theory

C₂₀H₁₆ClNO₄ (MW=369.802)

Mass spectrum: m/z=370/372 (M+H)⁺ (6) 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3,4-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.6)

Yield: 72% of theory

C₂₀H₁₅Cl₂NO₄ (MW=404.247)

Mass spectrum: m/z=404/406/408 (M+H)⁺ (7) 1,5-diacetyl-3-[(4-cyano-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-cyano-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.7)

Yield: 53% of theory

C₂₁H₁₆N₂O₄ (MW=360.367)

Mass spectrum: m/z=361 (M+H)⁺ (8) 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-trifluoromethyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.8)

Yield: 37% of theory

C₂₁H₁₆F₃NO₄ (MW=403.354)

Mass spectrum: m/z=404 (M+H)⁺ (9) 1,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-methoxy-methylidene]-2-indolinone

Prepared from 11,5-diacetyl-3-[(2,3-dihydro-benzo-[1,4]dioxin-6-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.9)

Yield: 52% of theory

R_(f)=0.82 (silica gel, methylene chloride/methanol 9:1)

C₂₂H₁₉NO₆ (MW=393.393)

Mass spectrum: m/z=394 (M+H)⁺ (10) 1,5-diacetyl-3-[(3-methoxy-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.10)

Yield: 48% of theory

R_(f)=0.40 (silica gel, methylene chloride/methanol 9:1)

C₂₁H₁₉NO₅ (MW=365.383)

Mass spectrum: m/z=366 (M+H)⁺ (11) 1,5-diacetyl-3-[(4-methoxy-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.11)

Yield: 85% of theory

R_(f)=0.35 (silica gel, methylene chloride/methanol 30:1)

C₂₁H₁₉NO₅ (MW=365.383)

Mass spectrum: m/z=366 (M+H)⁺ (12) 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone

Prepared from 1-diacetyl-5-propionyl-3-[(benzo[1,3]dioxol-5-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.12)

Yield: 98% of theory

R_(f)=0.63 (silica gel, methylene chloride/methanol 30:1)

C₂₂H₁₉NO₆ (MW=393.393)

Mass spectrum: m/z=394 (M+H)⁺ (13) 1,5-diacetyl-3-[(4-bromophenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-bromophenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.13)

Yield: 48% of theory (14) 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3,5-dichloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.14)

Yield: 44% of theory

R_(f)=0.86 (silica gel, methylene chloride/methanol 30:1)

C₁₉H₁₃Cl₂NO₄ (MW=390.221)

Mass spectrum: m/z=388/390/392 (Cl2, M+H)⁺ (15) 1,5-diacetyl-3-[(3,5-dimethoxy-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3,5-dimethoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.15)

Yield: 74% of theory

R_(f)=0.65 (silica gel, methylene chloride/methanol 30:1)

C₂₂H₂₁NO₆ (MW=395.409)

Mass spectrum: m/z=396 (M+H)⁺ (16) 1,5-diacetyl-3-[(2-chloro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(2-chloro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.16)

Yield: 54% of theory

C₂₀H₁₆ClNO₄ (MW=369.802)

Mass spectrum: m/z=370/372 (M+H)⁺ (17) 1,5-diacetyl-3-[(2-methoxy-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(2-methoxy-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.17)

Yield: 56% of theory

C₂₁H₁₉NO₅ (MW=365.383)

Mass spectrum: m/z=366 (M+H)⁺ (18) 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(2,6-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.18)

Yield: 59% of theory

C₂₀H₁₅F₂NO₄ (MW=3371.337)

Mass spectrum: m/z=372 (M+H)⁺ (19) 1,5-diacetyl-3-[(4-fluorophenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-fluorophenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.19)

Yield: 88% of theory

C₂₀H₁₆FNO₄ (MW=353.347)

Mass spectrum: m/z=354 (M+H)⁺ (20) 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(3,4-difluoro-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.20)

Yield: 23% of theory

C₂₀H₁₅F₂NO₄ (MW=371.334)

Mass spectrum: m/z=372 (M+H)⁺ (21) 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(2,2-difluoro-benzo[1,3]dioxol-5-yl)-hydroxy-methyl idene]-2-indolinone (Ex. V.21)

Yield: 6% of theory

C₂₁H₁₅F₂N O₆ (MW=415.346)

Mass spectrum: m/z=416 (M+H)⁺ (22) 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-(2-methoxycarbonyl-ethyl)-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.22)

Yield: 63% of theory

C₂₄H₂₃NO₆ (MW=421.447)

Mass spectrum: m/z=422 (M+H)⁺ (23) 1,5-diacetyl-3-[furan-3-yl-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[furan-3-yl-hydroxy-methylidene]-2-indolinone (Ex. V.25)

Yield: 59% of theory

C₁₈H₁₅NO₅ (MW=325.324)

Mass spectrum: m/z=326 (M+H)⁺

(24) 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-methoxy-methylidene]-2-indolinon

Prepared from 1,5-diacetyl-3-[(4-methoxycarbonylmethoxy-phenyl)-hydroxy-methylidene]-2-indolinone

Yield: 24% of theory

C₂₃H₂₁NO₇ (MW=423.415)

Mass spectrum: m/z=424 (M+H)⁺ (25) 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-methoxy-methylidene]-2-indolinone

Prepared from 1,5-diacetyl-3-[(4-methylsulphonyl-phenyl)-hydroxy-methylidene]-2-indolinone (Ex. V.28)

Yield: 20% of theory

C₂₁H₁₉NO₆S (MW=413.445)

Mass spectrum: m/z=414 (M+H)⁺ (26) 1,5-diacetyl-3-(1-methoxy-octylidene)-2-indolinone

Prepared from 1,5-diacetyl-3-(1-hydroxyl-octylidene)-2-indolinone (Ex. VIII)

Yield: 82% of theory

C₂₁H₂₇NO₄S (MW=357.443)

Mass spectrum: m/z=358 (M+H)⁺ (27) 1,5-diacetyl-3-(1-methoxy-heptylidene)-2-indolinone

Prepared from 1,5-diacetyl-3-(1-hydroxy-heptylidene)-2-indolinone (Ex. V.32) (28) 1,5-diacetyl-3-(1-methoxy-hexylidene)-2-indolinone

Prepared from 1,5-diacetyl-3-(1-hydroxy-hexylidene)-2-indolinone (Ex. V.33) (29) 1,5-diacetyl-3-(1-methoxy-3-methyl-butylidene)-2-indolinone

Prepared from 1,5-diacetyl-3-(1-hydroxy-3-methyl-butylidene)-2-indolinone (Ex. V.34)

EXAMPLE VII 1,5-diacetyl-3-[chloro-(Pyrazin-2-yl)-methylidene]-2-indolinone

1.2 g (3.7 mmol) 1,5-diacetyl-3-[(pyrazin-2-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.23) are dissolved in 50 ml dioxane and refluxed with 2 ml carbon tetrachloride and 2 g triphenylphosphine for 5 h. Then the mixture is left to cool and evaporated down. The residue is chromatographed through a silica gel column with methylene chloride/methanol 25:1, the corresponding fractions are combined and concentrated by rotary evaporation.

Yield: 400 mg (40% of theory)

R_(f)=0.70 (silica gel, methylene chloride/methanol 30:1)

C₁₇H₁₂ClN₃O₃ (MW=341.756)

Mass spectrum: m/z=342/344 (M+H)⁺ (CL)

The following compound is prepared analogously to Example VII: (1) 1,5-diacetyl-3-[chloro-(4-(2-dimethylamino-ethoxy)-phenyl)-methylidene]-2-indolinone

EXAMPLE VIII 1,5-diacetyl-3-(1-hydroxy-octylidene)-2-indolinone

4.3 g (20 mmol) 1,5-diacetyl-2-indolinone (Ex. II) are dissolved in 20 ml of dimethylformamide and 490 mg dimethylaminopyridine (DMAP) and 6 ml triethylamine added and the mixture is cooled in the ice bath. 3.8 ml (22 mmol) octanoic acid chloride in 20 ml of dimethylformamide are added to this solution and the mixture is stirred for a further 10 min. Then the reaction mixture is added to 150 ml of methylene chloride and 150 ml 1 N hydrochloric acid. The organic phase is separated off, dried over sodium sulphate and concentrated by rotary evaporation. The residue is chromatographed through a silica gel column with methylene chloride/methanol 95:5.

Yield: 740 mg (11% of theory)

C₂₀H₂₅NO₄ (MW=343.417)

Mass spectrum: m/z=344 (M)+

Preparation of the End Compounds:

Eluant:

-   A: methylene chloride/methanol 9:1 -   B: methylene chloride/methanol 4:1 -   C: methylene chloride/methanol/conc. ammonia 9:1:0.1 -   D: methylene chloride/methanol 30:1 -   E: methylene chloride/methanol/triethylamine 9:1:0.1

In the formulae in the Table the bond drawn free always represents the bond of the relevant group at the point of attachment in the molecule. The entry “—CH₃” in the Table thus denotes a methyl group and the entry

denotes an isobutyl group, i.e.—CH₂—CH(CH₃)₂.

EXAMPLE 1 5-acetyl-3-[(3-dimethylamino-propylamino)-phenyl-methylidene]-2-indolinone

0.2 g (0.57 mmol) of 1,5-diacetyl-3-(phenyl-ethoxy-methylidene)-2-indolinone (Ex. III) are suspended in 5 ml of dimethylformamide and stirred with 0.07 ml 3-dimethyl-amino-propylamine at 70° C. for 12 h. Then the mixture is left to cool, 2 ml of methanol and 1 ml 1 N sodium hydroxide solution are added and the mixture is stirred at ambient temperature for 30 min. Then water is added, and the resulting precipitate is filtered off, washed and dried. If necessary, the compound may be purified by chromatography on silica gel. A suitable eluant is methylene chloride/methanol 30:1.

Yield: 0.1 g (82% of theory)

R_(f)=0.39 (silica gel, methylene chloride/methanol/conc. ammonia 9:1:0.1)

C₂₂H₂₅N₃O₂ (MW=363.458)

Mass spectrum: m/z=364 (M+H)⁺

The following compounds of formula I are prepared analogously to Example 1:

R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 1.001 Me Ph

III 85.9 (M+H)⁺ =350 0.43 (A) 1.002 Me Ph

III 74.1 (M+H)⁺ =391 0.51 (A) 1.003 Me Ph

III 88.8 (M+H)⁺ =406 0.58 (A) 1.004 Me Ph

III 81.9 (M+H)⁺ =379 0.23 (D) 1.005 Me Ph

III 88.5 (M+H)⁺ =351 0.22 (D) 1.006 Me Ph

III 80.6 (M+H)⁺ =410 0.35 (C) 1.007 Me Ph

III 79.0 (M+H)⁺ =376 0.39 (C) 1.008 Me Ph

III 66.4 (M+H)⁺ =392 0.27 (C) 1.009 Me Ph

III 64.9 (M+H)⁺ =433 0.52 (C) 1.010 Me Ph

III 80.7 (M−H)⁻ =367 0.42 (A) 1.011 Me Ph

III 54.7 (M−H)⁻ =382 0.39 (A) 1.012 Me Ph

III 67.1 (M+H)⁺ =365 0.48 (A) 1.013 Me Ph

III 32.8 (M+H)⁺ =498 0.59 (A) 1.014 Me Ph

III 92.3 (M+H)⁺ =379 0.34 (A) 1.015 Me Ph

III 73.1 (M+H)⁺ =383 0.33 (A) 1.016 Me Ph

III 57.7 (M+H)⁺ =364 0.29 (A) 1.017 Me Ph

III 22.9 (M+H)⁺ =444 0.42 (A) 1.018 Me

VI.1 53.2 (M+H)⁺ =436 0.46 (B) 1.019 Me

VI.1 65.2 (M+H)⁺ =408 0.43 (A) 1.020 Me Ph

III 11.7 (M+H)⁺ =463 0.56 (A) 1.021 Me

VI.1 28.7 (M+H)⁺ =477 0.31 (A) 1.022 Me Ph

III 66.6 (M+H)⁺ =407 0.38 (A) 1.023 Me

VI.5 70.2 (M+H)⁺ =398/400 (Cl) 0.18 (A) 1.024 Me

VI.5 57.0 (M+H)⁺ =399/401 (Cl) 0.25 (A) 1.025 Me

VI.1 44.9 (M+H)⁺ =423 0.32 (A) 1.026 Me

VI.6 51.9 (M+H)⁺ =447/449/ 451 (Cl2) 0.30 (A) 1.027 Me

IV.6 24.5 (M+H)⁺ =423/434/ 436 (Cl2) 0.37 (C) 1.028 Me

VI.8 35.1 (M+H)⁺ =432 0.25 (A) 1.029 Me Ph Et III 98 (M+H)⁺ =307 0.44 (A) 1.030 Me Ph

III 90.6 (M+H)⁺ =317 0.31 (A) 1.031 Me Ph

III 90.3 (M+H)⁺ =349 0.48 (A) 1.032 Me Ph i-Pr III 77.5 (M+H)⁺ =321 0.46 (A) 1.033 Me Ph

III 78.4 (M+H)⁺ =335 0.33 (A) 1.034 Me Ph n-Pr III 56.7 (M+H)⁺ =321 0.31 (A) 1.035 Me Ph

III 93.3 (M+H)⁺ =319 0.32 (A) 1.036 Me

VI.9 72.1 (M+H)⁺ =437 0.38 (A) 1.037 Me

VI.8 40.2 (M+H)⁺ =447 0.75 (A) 1.038 Me

VI.11 76.9 (M+H)⁺ =409 0.36 (A) 1.039 Me

VI.10 80.3 (M+H)⁺ =409 0.36 (A) 1.040 Me

VI.13 67.7 (M−H)⁻ =440/442 (Br) 0.26 (A) 1.041 Me Ph

III 85.0 (M+H)⁺ =436 0.28 (A) 1.042 Me

VI.14 67.8 (M−H)⁻ =445/447/ 449 (Cl2) 0.25 (A) 1.043 Me

VI.15 71.0 (M+H)⁺ =439 0.27 (A) 1.044 Me

VI.16 75.5 (M+H)⁺ =369/371 (Cl) 0.33 (A) 1.045 Me

VI.17 62.2 (M+H)⁺ =365 0.05 (CH₂Cl₂/ MeOH 50:1) 1.046 Me

VI.19 68.1 (M+H)⁺ =353 0.46 (A) 1.047 Me

VI.19 59.4 (M+H)⁺ =397 0.45 (A) 1.048 Me

VI.20 13.8 (M+H)⁺ =371 0.54 (A) 1.049 Me

VI.20 51.4 (M+H)⁺ =415 0.56 (A) 1.050 Me

VI.21 38.5 (M+H)⁺ =415 0.31 (A) 1.051 Me

VI.21 33.8 (M−H)⁻ =457 0.46 (A) 1.052 Me

VI.21 22.4 (M−H)⁻ =443 0.37 (B) 1.053 Me

VI.7 78.6 (M+H)⁺ =404 0.53 (A) 1.054 Me

VI.7 90.3 (M+H)⁺ =389 0.53 (C) 1.055 Me

VI.7 83.8 (M+H)⁺ =360 0.36 (A) 1.056 Me

n-Pr VI.7 87.6 (M+H)⁺ =345 0.34 (A) 1.057 Me

VI.7 86.0 (M+H)⁺ =432 0.37 (A) 1.058 Me

VI.7 63.4 (M+H)⁺ =404 0.49 (A) 1.059 Me

VI.7 78.0 (M−H)⁻ =430 0.33 (A) 1.060 Me Ph t-Bu III 68.0 (M+H)⁺ =335 0.52 (A) 1.061 Me

VI.1 57.0 (M+H)⁺ =480 0.44 (A) 1.062 Me

VI.7 89.5 (M+H)⁺ =403 0.35 (A) 1.063 Me

VI.1 63.3 (M+H)⁺ =408 0.18 (A) 1.064 Me

VI.1 65.7 (M+H)⁺ =422 0.38 (A) 1.065 Me

VI.1 74.5 (M+H)⁺ =431 0.41 (A) 1.066 Me

IV.1 67.2 (M+H)⁺ =559/561 (Cl) 0.55 (A) 1.067 Me

VI.1 57.4 (M+H)⁺ =463 0.26 (A) 1.068 Me

VI.1 61.0 (M+H)⁺ =436 0.36 (A) 1.069 Me Ph

III 61.1 (M+H)⁺ =378 0.29 (A) 1.070 Me

VI.1 84.8 (M+H)⁺ =448 0.42 (A) 1.071 Me

VI.1 62.0 (M+H)⁺ =484 0.44 (A) 1.072 Me

VI.22 58.0 (M+H)⁺ =436 0.46 (A) 1.073 Me

VI.1 99.9 (M+H)⁺ =494 0.46 (A) 1.074 Me

VI.1 71.8 (M+H)⁺ =450 0.48 (A) 1.075 Me

VI.1 65.4 (M+H)⁺ =450 0.44 (A) 1.076 Me

VI.1 58.1 (M+H)⁺ =458 0.55 (A) 1.077 Me

VI.22 84.8 (M+H)⁺ =464 0.51 (C) 1.078 Me

VI.22 68.7 (M+H)⁺ =450 0.33 (C) 1.079 Me

VI.22 58.8 (M+H)⁺ =478 0.31 (C) 1.080 Me

VI.1 93.5 (M+H)⁺ =508 0.4 (A) 1.081 Me

VI.1 76.0 (M+H)⁺ =367 0.46 (A) 1.082 Me

VI.1 66.6 (M+H)⁺ =381 0.44 (A) 1.083 Me

VI.1 69.7 (M+H)⁺ =411 0.43 (A) 1.084 Me

VI.1 55.2 (M+H)⁺ =395 0.47 (A) 1.085 Me Ph H III 97.0 (M+H)⁺ =279 0.39 (C) 1.086 Me

H VI.3 85.1 (M+H)⁺ =324 0.53 (C) 1.087 Me

VI.12 51.5 (M+H)⁺ =437 0.39 (A) 1.088 Me

VI.19 66.6 (M+H)⁺ =381 0.43 (A) 1.089 Me

VI.19 69.1 (M+H)⁺ =422 0.09 (A) 1.090 Me

VI.19 28.8 (M+H)⁺ =484 0.40 (A) 1.091 Me

VI.19 92.4 (M+H)⁺ =480 0.12 (A) 1.092 Me

VI.1 67.0 (M+H)⁺ =451 0.45 (A) 1.093 Me

VI.1 55.0 (M+H)⁺ =451 0.45 (A) 1.094 Me

VI.1 72.0 (M+H)⁺ =367 0.47 (A) 1.095 Me

VI.1 84.0 (M+H)⁺ =316 0.41 (A) 1.096 Me

VI.1 66.0 (M−H)⁻ =440 0.53 (A) 1.097 Me Ph

III 60.0 (M−H)⁻ =396 0.52 (A) 1.098 Me Ph

III 59.0 (M+H)⁺ =398 0.60 (C) 1.099 Me Ph

III 85.0 (M+H)⁺ =399 0.59 (C) 1.100 Me Ph

III 84.0 (M+H)⁺ =422 0.52 (C) 1.101 Me Ph

III 70.0 (M+H)⁺ =399 0.25 (C) 1.102 Me Ph

III 73.0 (M+H)⁺ =412 0.42 (C) 1.103 Me Ph

III 89.0 (M+H)⁺ =384 0.41 (C) 1.104 Me Ph

III 86.0 (M+H)⁺ =397 0.58 (C) 1.105 Me Ph

III 81.0 (M+H)⁺ =411 0.44 (A) 1.106 Me Ph

III 49.0 (M+H)⁺ =411 0.43 (A) 1.107 Me Ph

III 40.0 (M+H)⁺ =411 0.41 (A) 1.108 Me Ph

III 73.0 (M+H)⁺ =439 0.46 (A) 1.109 Me Ph

III 90.0 (M+H)⁺ =425 0.49 (A) 1.110 Me Ph

III 90.0 (M+H)⁺ =441 0.40 (A) 1.111 Me Ph

III 93.0 (M+H)⁺ =442 0.32 (A) 1.112 Me Ph

III 78.0 (M+H)⁺ =335 0.50 (A) 1.113 Me Ph

III 89.0 (M+H)⁺ =412 0.50 (C) 1.114 Me Ph

III 87.0 (M+H)⁺ =436 n.d. 1.115 Me

VI.8 61.0 (M+H)⁺ =466 0.35 (A) 1.116 Me

VI.8 80.0 (M+H)⁺ =465 0.37 (A) 1.117 Me

VI.8 77.0 (M+H)⁺ =480 0.31 (A) 1.118 Me

VI.8 56.0 (M+H)⁺ =403 0.50 (A) 1.119 Me Ph

III 80.0 (M+H)⁺ =484 0.45 (A) 1.120 Me Ph

III 10.0 (M+H)⁺ =436 0.60 (A) 1.121 Me Ph

III 75.0 (M+H)⁺ =413 0.43 (A) 1.122 Me Ph

III 30.0 (M+H)⁺ =426 0.48 (A) 1.123 Me Ph

III 66.0 (M+H)⁺ =427 0.55 (A) 1.124 Me

VI.8 54.0 (M+H)⁺ =446 0.28 (A) 1.125 Me

VI.20 79.0 (M+H)⁺ =371 0.21 (A) 1.126 Me

VI.20 77.0 (M+H)⁺ =385 0.20 (A) 1.127 Me Et

III.3 73.0 (M+H)⁺ =349 0.44 (E) 1.128 Me Et

III.3 69.0 (M+H)⁺ =387 0.48 (E) 1.129 Me n-Pr

III.4 94.0 (M−H)⁻ =361 0.47 (A) 1.130 Me n-Pr

III.4 93.0 (M+H)⁺ =301 0.51 (A) 1.131 Me n-Pr

III.4 74.0 (M+H)⁺ =301 0.63 (A) 1.132 Me n-Pr

III.4 47.0 (M+H)⁺ =344 0.31 (C) 1.133 Me n-Pr

III.4 38.0 (M+H)⁺ =330 0.62 (C) 1.134 Me n-Pr

III.4 45.0 (M+H)⁺ =358 0.51 (C) 1.135 Me n-Bu

III.5 94.0 (M+H)⁺ =377 0.54 (E) 1.136 Me n-Bu

III.5 86.0 (M+H)⁺ =315 0.69 (E) 1.137 Me n-Bu

III.5 81.0 (M+H)⁺ =315 0.69 (E) 1.138 Me n-Bu

III.5 59.0 (M+H)⁺ =358 0.22 (A) 1.139 Me n-Bu

III.5 55.0 (M+H)⁺ =344 0.22 (A) 1.140 Me n-Bu

III.5 42.0 (M+H)⁺ =372 0.12 (A) 1.141 Me

VI.1 69.8 (M+H)⁺ =465 0.36 (A) 1.142 Me

VI.25 68.0 (M+H)⁺ =413 0.52 (A) 1.143 Me

VI.26 79.6 (M+H)⁺ =400 0.08 (A) 1.144 Me

VI.26 62.1 (M+H)⁺ =357 0.51 (A) 1.145 Me

VI.27 76.4 (M+H)⁺ =386 0.11 (A) 1.146 Me

VI.28 22.0 (M+H)⁺ =372 0.23 (C) 1.147 Me

VI.29 12.0 (M+H)⁺ =358 0.16 (C) 1.148 Et Et

III.7 70.0 (M+H)⁺ =344 0.11 (A) 1.149 Et Et

III.7 87.0 (M+H)⁺ =363 0.45 (A) 1.150 n- C₅H₁₁ Et

III.8 73.0 (M+H)⁺ =405 0.47 (A) 1.151 Me

VI.28 75.0 (M+H)⁺ =486 0.27 (C) 1.152 Me

VI.28 58.0 (M+H)⁺ =391 0.46 (A) 1.153 Me

VI.29 37.0 (M+H)⁺ =315 0.66 (A) 1.154 Me

VI.29 51.0 (M+H)⁺ =372 0.24 (A) 1.155 Me

VI.29 50.0 (M+H)⁺ =377 0.47 (C)

EXAMPLE 2 5-acetyl-3-[benzo[3]dioxol-5-yl-(3-methylamino-propylamino)-methylidene]-2-indolinone

680 mg (1.38 mmol) 5-acetyl-3-[benzo[1.3]dioxol-5-yl-(3-(N-tert-butoxycarbonyl-N-methyl-amino)-propylamino)-methylidene]-2-indolinone (Example 1.073) are added batchwise to a solution of 2 ml trifluoroacetic acid in 20 ml methylene chloride and stirred for 5 h at ambient temperature. Then the mixture is evaporated down, the residue is taken up in methylene chloride, made alkaline with 1 N sodium hydroxide solution and then the organic phase is separated off, dried over sodium sulphate and evaporated down.

Yield: 210 mg (38% of theory)

R_(f)=0.05 (silica gel, methylene chloride/methanol 9:1)

C₂₂H₂₃N₃O₄ (MW=393.441)

Mass spectrum: m/z=394 (M+H)⁺

The following compounds of formula I are prepared analogously to Example 2: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 2.001 Me Ph

1.013 65.1 (M+H)⁺ =398 0.14 (B) 2.002 Me Ph

4.014 52.9 (M+H)⁺ =433 0.48 (C) 2.003 Me Ph

4.016 56.7 (M+H)⁺ =419 0.38 (C) 2.004 Me Ph

1.041 53.2 (M+H)⁺ =336 0.40 (C) 2.005 Me

1.061 97.3 (M+H)⁺ =380 0.08 (A) 2.006 Me

1.080 81.1 (M+H)⁺ =408 0.1 (A) 2.007 Me Ph

1.114 82.0 (M+H)⁺ =336 0.32 (C)

EXAMPLE 3 5-acetyl-3-[(carboxymethyl-amino)-phenyl-methylidene]-2-indolinone

88 mg (0.25 mmol) 5-acetyl-3-[(methoxycarboxymethyl-amino)-phenyl-methylidene]-2-indolinone (Example 1.005) are suspended in 0.5 ml 1 N sodium hydroxide solution and 5 ml of methanol and refluxed for 4 h. Then the mixture is cooled, 0.5 ml 1 N hydrochloric acid are added and the precipitate is removed by suction filtering.

Yield: 81 mg (95% of theory)

C₁₉H₆N₂O₄ (MW=336.345)

Mass spectrum: m/z=337 (M+H)⁺

The following compounds of formula I are prepared analogously to Example 3: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 3.001 Me Ph

1.004 91.3 (M+H)⁺ =351 not determined 3.002 Me Ph

1.014 34.6 (M+H)⁺ =365 0.19 (A) 3.003 Me Ph

1.012 88.5 (M−H)⁻ =349 0.47 (A +glacial acetic acid) 3.004 Me Ph

1.022 57.0 (M+H)⁺ =393 0.26 (A) 3.005 Me

1.022 85.5 (M+H)⁺ =409 0.31 (A) 3.006 Me

1.026 42.5 (M−H)⁻ =431/433/ 435 (Cl2) 0.31 (A) 3.007 Me

1.036 82.7 (M−H)⁻ =421 0.33 (A) 3.008 Me

1.037 41.3 (M−H)⁻ =431 0.22 (A) 3.009 Et

1.087 82.6 (M+H)⁺ =423 0.78 (B) 3.010 Me

1.038 93.1 (M−H)⁻ =393 0.7 (B) 3.011 Me

1.039 79.2 (M−H)⁻ =393 0.33 (A) 3.012 Me

1.042 90.9 (M+H)⁺ =433/435/ 437 (Cl2) 0.32 (A) 3.013 Me

1.043 77.5 (M+H)⁺ =425 0.27 (A) 3.014 Me

1.047 79.4 (M+H)⁺ =383 0.38 (A) 3.015 Me

1.049 78.4 (M+H)⁺ =401 0.36 (A) 3.016 Me

7.004 19.5 (M+H)⁺ =394 0.09 (A +glacial acetic acid) 3.017 Me

7.012 95.5 (M+H)⁺ =380 0.05 (A +glacial acetic acid) 3.018 Me

7.010 56.3 (M+H)⁺ =442 0.02 (C) 3.019 Me

6.006 98 (M+H)⁺ =436 0.39 (A +glacial acetic acid) 3.020 Me

1.072 82.5 (M+H)⁺ =442 0.45 (MeOH) 3.021 Me

5.014 93.4 (M+H)⁺ =408 0.39 (MeOH) 3.022 Me

1.077 85.9 (M+H)⁺ =450 0.24 (MeOH) 3.023 Me

1.078 72.4 (M+H)⁺ =436 0.22 (MeOH) 3.024 Me

1.079 57.4 (M−H)⁻ =462 0.15 (MeOH) 3.025 Me

8.004 89.0 (M+H)⁺ =450 0.56 (A)

EXAMPLE 4 5-acetyl-3-{[3-(N,N-bis-(2-hydroxyethyl)-carbamoyl)-propylamino]-phenyl-methylene}-2-indolinone

100 mg (0.27 mmol) 5-acetyl-3-[3-(carboxy-propylamino)-phenyl-methylidene]-2-indolinone (Ex. 3.002) are stirred with 45 mg CDI (carbonyldiimidazole) in 3 ml of tetrahydrofuran for 3 h at 60° C. Then 30 mg diethanolamine (0.28 mmol) are added and the mixture is stirred overnight at ambient temperature. Then the mixture is evaporated down, the residue is taken up in ethyl acetate, washed with water and the organic phase is dried over sodium sulphate. Then it is concentrated by rotary evaporation.

Yield: 42 mg (34% of theory)

R_(f)=0.23 (silica gel, methylene chloride/methanol 9:1)

C₂₅H₂₉N₃O₅ (MW=451.52)

Mass spectrum: m/z=452 (M+H)⁺

The following compounds of formula I are prepared analogously to Example 4: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 4.001 Me Ph

3.001 29.2 (M+H)⁺ =421 0.12 (CH₂Cl₂/ MeOH 1:1) 4.002 Me Ph

3.001 54.8 (M+H)⁺ =449 0.27 (C) 4.003 Me Ph

3.001 29.0 (M+H)⁺ =364 0.24 (A) 4.004 Me Ph

3.001 16.0 (M+H)⁺ =438 0.16 (A) 4.005 Me Ph

3.002 38.7 (M+H)⁺ =378 0.35 (C) 4.006 Me Ph

3.002 24.9 (M+H)⁺ =440 0.33 (A) 4.007 Me Ph

3.002 25.9 (M+H)⁺ =392 0.54 (A) 4.008 Me Ph

3.002 56.9 (M−H)⁻ =390 0.57 (A) 4.009 Me Ph

3.002 59.0 (M+H)⁺ =435 0.53 (C) 4.010 Me Ph

3.002 90.2 (M+H)⁺ =447 0.28 (A) 4.011 Me Ph

3.002 26.2 (M+H)⁺ =533 0.47 (A) 4.012 Me Ph

3.002 47.5 (M+H)⁺ =463 0.34 (C) 4.013 Me Ph

3.001 14.8 (M+H)⁺ =519 0.47 (A) 4.014 Me Ph

3.002 51.0 (M+H)⁺ =364 0.72 (A)

EXAMPLE 5 5-acetyl-3-[(4-aminomethyl-phenyl)-(3-dimethylamino-propylylamino)-methylidene]-2-indolinone

200 mg (0.51 mmol) 5-acetyl-3-[(4-cyano-phenyl)-(3-dimethylamino-propylamino)-methylidene]-2-indolinone (Example 1.054) are dissolved in 13 ml of methanolic ammonia, combined with 80 mg Raney nickel and hydrogenated at ambient temperature for 6 h at a pressure of 50 psi. Then the catalyst is filtered off and the solution is evaporated down. The residue is chromatographed through a silica gel column with methylene chloride:methanol 30:1. The desired fraction is collected and evaporated down.

Yield: 180 mg (89% of theory)

R_(f)=0.19 (silica gel, methylene chloride/methanol/conc. ammonia 9:1:0.1)

C₂₃H₂₈N₄O₂ (MW=392.5)

Mass spectrum: m/z=393 (M+H)⁺

The following compounds of formula I are prepared analogously to Example 5: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 5.001 Me

1.053 68.9 (M+H)⁺ =408 0.39 (C) 5.002 Me

1.055 45.0 (M+H)⁺ =364 0.5 (C) 5.003 Me

n-Pr 1.056 49.4 (M+H)⁺ =350 0.44 (C) 5.004 Me

1.057 84.9 not determined 0.43 (C) 5.005 Me

1.058 57.4 (M+H)⁺ =394 0.23 (C) 5.006 Me

1.062 88.6 (M+H)⁺ =407 0.26 (C) 5.007 Me

1.059 68.7 (M+H)⁺ =436 0.53 (C)

EXAMPLE 6 5-acetyl-3-{benzo[1.3]dioxol-5-yl-[3-(N-methyl-N-acetyl-amino)-propylamino]-methylene}-2-indolinone

150 mg (0.38 mmol) 5-acetyl-3-[benzo[1.3]dioxol-5-yl-(3-methylamino-propylamino)-methylidene]-2-indolinone (Example 2) are placed in 4 ml methylene chloride and combined with 54 μl triethylamine. 28 μl (0.39 mmol) acetylchloride are added dropwise to this solution while cooling with ice and the mixture is stirred for 10 min. Then the mixture is left to warm up to ambient temperature and stirred for 1 h. The solution is then washed with water, the organic phase is dried over sodium sulphate, suction filtered and concentrated by rotary evaporation. The residue is eluted through a silica gel column with ethyl acetate/cyclohexane/methanol 9:9:2. The desired fraction is collected and evaporated down.

Yield: 45 mg (27% of theory)

R_(f)=0.51 (silica gel, methylene chloride/methanol 9:1)

C₂₄H₂₅N₃O₅ (MW=435.478)

Mass spectrum: m/z=436 (M+H)⁺

The following compounds are prepared analogously to Example 6: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 6.001 Me Ph

2.004 24.8 (M+H)⁺ =440 0.30 (C) 6.002 Me Ph

2.004 10.1 (M+H)⁺ =450 0.45 (ethyl acetate/ MeOH 80:1) 6.003 Me

5.000 53.4 (M+H)⁺ =435 0.30 (C) 6.004 Me

5.001 45.4 (M+H)⁺ =450 0.54 (C) 6.005 Me

5.002 19.2 (M+H)⁺ =406 0.41 (C) 6.006 Me

n-Pr 5.003 71.4 (M+H)⁺ =392 0.53 (C) 6.007 Me

5.005 81.3 (M+H)⁺ =436 0.35 (C) 6.008 Me

5.004 39.6 (M+H)⁺ =478 0.56 (C) 6.009 Me

5.006 24.2 (M+H)⁺ =449 0.21 (A) 6.010 Me

5.007 56.9 (M+H)⁺ =478 0.50 (A) 6.011 Me Ph

2.004 25.3 (M+H)⁺ =414 0.28 (C) 6.012 Me Ph

2.007 67.0 (M+H)⁺ =454 0.41 (A)

EXAMPLE 7 5-acetyl-3-[(Pyrazin-2-yl)-isobutylamino-methylidene]-2-indolinone

80 mg (0.23 mmol) 1.5-diacetyl-3-[chloro-(pyrazin-2-yl)-methylidene]-2-indolinone (Ex. VII) in 4 ml of tetrahydrofuran are stirred for 2 h at ambient temperature with 0.05 ml triethylamine and 0.022 g isobutylamine. The acetyl-protected intermediate product is combined with 0.8 ml of conc. ammonia without purification and stirred for half an hour at ambient temperature. Then it is evaporated down and the residue is chromatographed through a silica gel column using methylene chloride/methanol 40:1 as eluant.

Yield: 29 mg (36% of theory)

R_(f)=0.56 (silica gel, methylene chloride/methanol 9:1)

C₁₉H₂₀N₄O₂ (MW=336.393)

Mass spectrum: m/z=337 (M+H)⁺

EXAMPLE 8 5-acetyl-3-[(pyridin-4-yl)-(isobutylamino)-methylidene]-2-indolinone

500 mg (1.55 mmol) 1.5-diacetyl-3-[(pyridin-4-yl)-hydroxy-methylidene]-2-indolinone (Ex. V.24) in 2.4 ml hexamethyldisilazane are heated to 120° C. with 0.23 g 4-amino-1-methylpiperidine for 3 h. Then the mixture is left to cool and 10 ml of methanol and 32 mg sodium methoxide are added and the mixture is stirred for 1 h at ambient temperature. Then it is evaporated down and the residue is chromatographed through a silica gel column with methylene chloride/methanol 12:1 as eluant.

Yield: 160 mg (31% of theory)

R_(f)=0.56 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₂₁N₃O₂ (MW=335.405)

Mass spectrum: m/z=336 (M+H)⁺

The following compound of formula I is prepared analogously to Example 8: R_(f) value Educt Mass (silica Yield spectrum gel) Example R¹ R² R³ [%] (ES) m/z (eluant) 8.001 Me

V.26 26.4 (M+H)⁺ =463 0.58 (C) 8.002 Me

V.26 38.8 (M+H)⁺ =420 0.60 (A) 8.003 Me

V.26 13.6 (M+H)⁺ =449 0.49 (C) 8.004 Me

V.26 43.8 (M+H)⁺ =464 0.54 (C) 8.005 Me

V.29 21.0 (M+H)⁺ =493 0.41 (B) 8.006 Me

V.29 12.0 (M+H)⁺ =436 0.85 (B) 8.007 Me

V.30 trimethyl- imidazole 70.0 (M+H)⁺ =450 0.68 (C) 8.008 Me

V.30 trimethyl- imidazole 54.0 (M+H)⁺ =513 0.68 (C)

EXAMPLE 9 5-acetyl-3-[furan-3-yl-isobutylamino-methylidene]-2-indolinone

200 mg (0.65 mmol) 1.5-diacetyl-3-[furan-3-yl-methoxy-methylidene]-2-indolinone (Ex. VI.23) are suspended in 5 ml of dimethylformamide and stirred for 2 h with 61 mg isobutylamine at ambient temperature. The acetyl-protected intermediate product is combined with 1 ml of conc. ammonia without purification and stirred at ambient temperature for 30 min. Then the mixture is evaporated down and the residue is chromatographed through a silica gel column with the eluant methylene chloride/methanol 4:1.

Yield: 78 mg (37% of theory)

R_(f)=0.2 (silica gel, methylene chloride/methanol 30:1)

C₁₉H₂₀N₂O₃ (MW=324.383)

Mass spectrum: m/z=325 (M+H)⁺

EXAMPLE 10 5-acetyl-3-[1-(N′,N′-dimethylhydrazino)-1-(4-trifluoromethyl-phenyl)-methylidene]-2-indolinone

0.2 g (0.4 mmol) 1.5-diacetyl-3-[(4-trifluoromethylphenyl)-ethoxy-methylidene]-2-indolinone (Ex. VI.8) are suspended in 4 ml of dimethylformamide and stirred with 0.038 ml dimethylhydrazine at ambient temperature for 5 h. Then 2 ml of 1 N sodium hydroxide solution are added and the mixture is stirred at ambient temperature for 30 min. The reaction mixture is poured onto 10 ml of water, the precipitate is filtered off and dried in the desiccator.

If desired the product may be purified through a silica gel column with methylene chloride/methanol 30:1 as eluant.

Yield: 0.11 g (57% of theory)

R_(f)=0.55 (silica gel, methylene chloride/methanol 9:1)

C₂₀H₁₈F₃N₃O₂ (MW=389.371)

Mass spectrum: m/z=390 (M+H)⁺

The following compounds are prepared analogously to Example 10: educt Example R¹ R² R³ Yield [%] Mass spectrum (ES) m/z R_(f) value (silica gel) (eluant) 10.001 Me

VI.20 42.0 (M + H)⁺ = 358 0.59 (A) 10.002 Me

VI.19 36.0 (M + H)⁺ = 340 0.24 (A) 10.003 Me

VI.10 16.0 (M + H)⁺ = 352 0.48 (A) 10.004 Et

IV.3 81.0 (M + H)⁺ = 336 0.34 (A) 10.005 Me

VI.8 35.0 (M + H)⁺ = 466 0.54 (A) 10.006 Me Et

III.3 63.0 (M + H)⁺ = 274 0.79 (A) 10.007 Me

VI.8 14.0 (M + H)⁺ = 438 0.50 (A) 10.008 Me

VI.8 45.0 (M + H)⁺= 404 0.41 (A) 10.009 Me

VI.8 43.0 (M + H)⁺= 466 0.43 (A) 10.010 Me

VI.8 29.0 (M + H)⁺ = 460 0.43 (A) 10.011 Me

VI.8 67.0 (M + H)⁺ = 480 0.54 (A) 10.012 Me Et

III.3 53.0 (M + H)⁺ = 322 0.53 (A) 10.013 Me Et

III.3 58.0 (M + H)⁺ = 350 0.40 (A) 10.014 Me Et

III.3 62.0 (M + H)⁺ = 350 0.47 (A) 10.015 Me

VI.28 72.0 (M + H)⁺ = 316 0.67 (C) 10.016 Me

VI.29 42.0 (M + H)⁺ = 302 0.47 (C)

EXAMPLE 11

Coated Tablets Containing 75 mg of Active Substance 1 tablet core contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethylcellulose 15.0 mg magnesium stearate 1.5 mg 230.0 mg Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose and half the specified amount of magnesium stearate. Blanks 13 mm in diameter are produced in a tablet-making machine and these are then rubbed through a screen with a mesh size of 1.5 mm using a suitable machine and mixed with the rest of the magnesium stearate. This granulate is compressed in a tablet-making machine to form tablets of the desired shape. Weight of core: 230 mg die: 9 mm, convex

The tablet cores thus produced are coated with a film consisting essentially of hydroxypropylmethylcellulose. The finished film-coated tablets are polished with beeswax.

Weight of coated tablet: 245 mg.

EXAMPLE 12

Tablets Containing 100 mg of Active Substance

Composition: 1 tablet contains: active substance 100.0 mg lactose 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg Method of Preparation:

The active substance, lactose and starch are mixed together and uniformly moistened with an aqueous solution of the polyvinylpyrrolidone. After the moist composition has been screened (2.0 mm mesh size) and dried in a rack-type drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to form tablets. Weight of tablet: 220 mg Diameter: 10 mm, biplanar, facetted on both sides and notched on one side.

EXAMPLE 13

Tablets Containing 150 mg of Active Substance

Composition: 1 tablet contains: active substance 150.0 mg powdered lactose 89.0 mg corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mg 300.0 mg Preparation:

The active substance mixed with lactose, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a screen with a mesh size of 1.5 mm. The granules, dried at 45° C., are passed through the same screen again and mixed with the specified amount of magnesium stearate. Tablets are pressed from the mixture. Weight of tablet: 300 mg die: 10 mm, flat

EXAMPLE 14

Hard Gelatine Capsules Containing 150 mg of Active Substance 1 capsule contains: active substance 150.0 mg corn starch (dried approx. 180.0 mg lactose (powdered) approx. 87.0 mg magnesium stearate 3.0 mg approx. 420.0 mg Preparation:

The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The finished mixture is packed into size 1 hard gelatine capsules. Capsule filling: approx. 320 mg Capsule shell: size 1 hard gelatine capsule.

EXAMPLE 15

Suppositories Containing 150 ma of Active Substance 1 suppository contains: active substance 150.0 mg polyethyleneglycol 1500 550.0 mg polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2,000.0 mg Preparation:

After the suppository mass has been melted the active substance is homogeneously distributed therein and the melt is poured into chilled moulds.

EXAMPLE 16

Suspension Containing 50 mg of Active Substance 100 ml of suspension contain: active substance 1.00 g carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose 10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring 0.30 g dist. water ad 100 ml Preparation:

The distilled water is heated to 70° C. The methyl and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved therein with stirring. The solution is cooled to ambient temperature and the active substance is added and homogeneously dispersed therein with stirring. After the sugar, the sorbitol solution and the flavouring have been added and dissolved, the suspension is evacuated with stirring to eliminate air.

5 ml of suspension contain 50 mg of active substance.

EXAMPLE 17

Ampoules Containing 10 ma Active Substance

Composition: active substance 10.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 2.0 ml Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 2 ml ampoules.

EXAMPLE 18

Ampoules Containing 50 ma of Active Substance

Composition: active substance 50.0 mg 0.01 N hydrochloric acid q.s. double-distilled water ad 10.0 ml Preparation:

The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, filtered sterile and transferred into 10 ml ampoules. 

1. Compounds of general formula

wherein R¹ denotes a straight-chain or branched C₁₋₅-alkyl group wherein the hydrogen atoms may be wholly or partly replaced by fluorine atoms, or an aryl group optionally substituted by a fluorine, chlorine or bromine atom, while by an aryl group is meant a phenyl or naphthyl group, R² denotes a C₁₋₇-alkyl or C₃₋₇-cycloalkyl group, a 5- or 6-membered heteroaryl group with one to three heteroatoms selected from the group N, S and O, while both the heteratoms and the substituents may be identical or different, optionally substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C₁₋₃-alkyl or C₁₋₃-alkoxy groups, a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, a phenyl group, to which is anellated another phenyl ring or a 5- or 6-membered heteroaromatic ring with one to three heteroatoms selected from the group N, S and O, while the heteratoms may be identical or different, and the bicyclic group may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or one or two nitro, cyano, amino, C₁₋₃-alkyl or C₁₋₃-alkoxy groups and the substituents may be identical or different, or a phenyl group which may be substituted by one to three fluorine, chlorine, bromine or iodine atoms or by one to three C₁₋₃-alkyl, nitro, cyano, amino, di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino, phenylcarbonylamino, C₁₋₃-alkylsulphonylamino, arylsulphonylamino, trifluoromethyl, C₁₋₃alkylsulphonyl, carboxy, C₁₋₃-alkoxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, C₁₋₃-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, hydroxy-carbonyl-C₁₋₃-alkyl-aminocarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-amino-carbonyl-C₁₋₃-alkoxy, C₁₋₃-alkyl-amino-carbonyl-C₁₋₃-alkoxy, carboxy-C₁₋₃-alkoxy, C₁₋₃-alkyloxy-carbonyl-C₁₋₃-alkoxy, carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl, C₁₋₃-alkoxy-carbonyl-amino-C₁₋₃-alkyl, amino-C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl-amino-C₁₋₃-alkyl, phthalimido, pyrrolyl or mono- or di-(C₁₋₃-alkyl)-pyrrolyl groups, while the substituents are identical or different, and R³ denotes a hydrogen atom, a straight-chain or branched C₁-alkyl group which may be substituted by one to three carboxy, C₁₋₄-alkoxy-carbonyl, aminocarbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-amino-carbonyl, N-[di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)]-N-(C₁₋₃-alkyl)-amino-carbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aryl-C₁₋₃-alkyl-aminocarbonyl, heteroaryl-C₁₋₃-alkyl-aminocarbonyl, N-(aryl)—N-(C₁₋₃-alkyl)-aminocarbonyl, N-(heteroaryl)-N-(C₁₋₃-alkyl)-aminocarbonyl, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl, aryl or heteroaryl groups or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group, while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group may be replaced in position 3 or 4 by an —NH—, —N(C₁₋₃-alkyl)- or —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group, a straight-chain or branched C₂₋₆-alkyl group which is substituted from position 2 onwards by one to three hydroxy, C₁₋₃-alkoxy, aryloxy, heteroaryloxy, amino-C₁₋₃-alkyloxy, C₁₋₃-alkyl-amino-C₁₋₃-alkyloxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, ω-hydroxy-C₂₋₃-alkoxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino, heteroaryl-carbonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino, N—(C₁₋₃-alkyl)-N-(heteroaryl-carbonyl)-amino, C₁₋₄-alkoxy-carbonylamino, N—(C₁₋₃-alkyl)-N-(C₁₋₄-alkoxy-carbonyl)-amino, arylcarbonylamino, N-(C₁₋₃-alkyl)-N-(aryl-carbonyl)-amino, (ω-hydroxy-C₂₋₃-alkyl)-amino, di-(ω-hydroxy-C₂₋₃-alkyl)-amino, arylamino, heteroarylamino, C₁₋₃-alkylsulphonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino, C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino, (C₁₋₃-alkyl-amino)-carbonyl-amino, [di-(C₁₋₃-alkyl)-amino]-carbonyl-amino, (C₁₋₃-alkyl-amino)-C₁₋₃-alkyl-carbonyl-amino, [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyl-carbonyl-amino, N-(aryl-C₁₋₃-alkyl-carbonyl)-N-(C₁₋₃-alkyl)-amino, N-(C₁₋₃-alkyl)-N-[(C₁₋₃-alkyl-amino)-carbonyl]-amino or N-(C₁₋₃-alkyl)-N-{[di-(C₁₋₃-alkyl)-amino]-carbonyl}-amino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C₁₋₄-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, arylamino-carbonyl, heteroarylaminocarbonyl-, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl-, aryl or heteroaryl group or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneimino-carbonyl group, while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group, a C₂₋₄-alkenyl or C₂₋₄-alkynyl group, while between the nitrogen atom to which R³ is bound and the multiple bond there is at least one sp³-hybridised carbon atom and the alkenyl or alkynyl group may be substituted by one to three C₁₋₃-alkyl groups, a C₁₋₅-alkyl group in the methylene group which is adjacent to the nitrogen atom to which R³ is bound may be replaced by an —NH—, or a —N(C₁₋₃-alkyl)-group or by an oxygen atom, a C₁₋₄-alkyloxy group or an amino group which may be substituted by one or two C₁₋₃-alkyl, aryl, aryl-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₄-alkyloxy-carbonyl, arylcarbonyl or aryl-C₁₋₃-alkyl-carbonyl groups, while the substituents may be identical or different, while the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 2. Compounds of general formula I according to claim 1, wherein R² and R³ are defined as in claim 1 and R¹ denotes a methyl, ethyl, n-propyl, isopropyl, n-pentyl, trifluoromethyl or phenyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 3. Compounds of general formula I according to claim 2, wherein R¹ denotes a methyl or ethyl group, R² denotes an ethyl, propyl, butyl or pentyl group, a pyridinyl, furanyl or pyrazinyl group, a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or a phenyl group which may be substituted by one or two fluorine, chlorine, bromine or iodine atoms or by one or two C₁₋₃-alkyl, nitro, cyano, amino, C₁₋₃-alkylcarbonylamino, phenylcarbonylamino, C₁₋₃-alkylsulphonylamino, trifluoromethyl, carboxy, C₁₋₃-alkoxy, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkyloxy, C₁₋₃-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, hydroxycarbonyl-C₁₋₃-alkyl-aminocarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₃-alkyl-aminocarbonyl, di-(C₁₋₃-alkyl)-amino-C₁₋₃-alkylaminocarbonyl, carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl, amino-C₁₋₃-alkyl or C₁₋₃-alkyl-carbonylamino-C₁₋₃-alkyl groups, while the substituents are identical or different, and R³ denotes a hydrogen atom, a straight-chain or branched C₁₋₆-alkyl group which may be substituted by a carboxy, C₁₋₄-alkoxy-carbonyl, phenyl, pyridinyl, indolyl, imidazolyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group, while the above-mentioned phenyl group may optionally be substituted by a nitro, cyano, C₁₋₃-alkyloxy, [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group and in the above-mentioned cycloalkyleneimino and cycloalkyleneiminocarbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 by a carbonyl group, a straight-chain or branched C₂₋₆-alkyl group which is substituted from position 2 onwards by a hydroxy, C₁₋₃-alkoxy, ω-hydroxy-C₂₋₃-alkoxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino, C₁₋₄-alkoxy-carbonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₄-alkoxy-carbonyl)-amino, phenylcarbonylamino, N-(C₁₋₃-alkyl)—N-(phenylcarbonyl)-amino, di-(ω-hydroxy-C₂₋₃-alkyl)-amino, pyridinylamino, nitro-pyridinyl-amino, chloro-trifluoromethyl-pyridinylamino, C₁₋₃-alkylsulphonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino or C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino group and may optionally additionally be substituted from position 1 onwards by a carboxy, C₁₋₄-alkoxy-carbonyl, phenyl, pyridinyl, imidazolyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(ω-hydroxy-C₂₋₃-alkyl)-aminocarbonyl or by a 5 to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group, while in the above-mentioned cycloalkyleneimino or cycloalkyleneimino-carbonyl group a methylene group in position 3 or 4 may be replaced by an —NH—, —N(C₁₋₃-alkyl)- or —N(C₁₋₄-alkoxy-carbonyl)-group or by an oxygen or sulphur atom and/or in position 2, 3 or 4 may be replaced by a carbonyl group, and the above-mentionedn phenyl groups may optionally be substituted by an amino-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group, or or represent a propenyl or propynyl group, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 4. Compounds of general formula I according to claim 3, wherein R¹ denotes a methyl group, R² denotes an ethyl, propyl, butyl or pentyl group, a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy, ethylenedioxy or difluoromethylenedioxy group, or a phenyl group which may be substituted by one or two fluorine, chlorine or bromine atoms or by one or two trifluoromethyl, nitro, cyano, C₁₋₃-alkoxy, carboxy-C₁₋₃-alkyl, C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl, amino-C₁₋₃-alkyl or C₁₋₃-alkyl-carbonylamino-C₁₋₃-alkyl-groups, while the substituents are identical or different, and R³ denotes a straight-chain or branched C₁₋₅-alkyl group which may be substituted by a carboxy, C₁₋₄-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl, pyridinylaminocarbonyl, di-(2-hydroxy-ethyl)-aminocarbonyl, piperazinylcarbonyl, 4-(C₁₋₃-alkyl)-piperazinyl-carbonyl, 4-(C₁₋₄-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group, while the phenyl group may optionally be substituted by a nitro, cyano, C₁₋₃-alkyloxy, [di-(C₁₋₃-alkyl)-amino]-C₁₋₃-alkyloxy, amino-C₁₋₃-alkyl or C₁₋₄-alkoxy-carbonylamino-C₁₋₃-alkyl group, a C₂₋₅-alkyl group which is terminally substituted by a hydroxy, C₁₋₃-alkoxy, phenyloxy, 2-hydroxy-ethoxy, amino, C₁₋₃-alkylamino, di-(C₁₋₃-alkyl)-amino, C₁₋₃-alkyl-carbonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkyl-carbonyl)-amino, C₁₋₄-alkoxy-carbonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₄-alkoxy-carbonyl)-amino, phenylcarbonylamino, N-(C₁₋₃-alkyl)-N-(phenylcarbonyl)-amino, pyridinylamino, nitro-pyridinyl-amino, di-(2-hydroxy-ethyl)-amino, 3-chloro-5-trifluoromethyl-pyridin-2-yl-amino, C₁₋₃-alkylsulphonylamino, N-(C₁₋₃-alkyl)-N-(C₁₋₃-alkylsulphonyl)-amino, C₁₋₃-alkoxy-carbonyl-C₁₋₃-alkyl-carbonylamino, indolyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, morpholinyl, piperazinyl or 4-(C₁₋₃-alkyl)-piperazinyl group and may optionally additionally be substituted from position 1 onwards by a carboxy, C₁₋₄-alkoxy-carbonyl, C₁₋₃-alkylaminocarbonyl, di-(C₁₋₃-alkyl)-aminocarbonyl, phenylaminocarbonyl, di-(2-hydroxy-ethyl)-amino-carbonyl, piperazinylcarbonyl, 4-(C₁₋₃-alkyl)-piperazinyl-carbonyl, 4-(C₁₋₄-alkoxy-carbonyl)-piperazinyl-carbonyl, phenyl, pyridinyl or imidazolyl group, or an amino group which may be substituted by one or two C₁₋₃-alkyl, aryl, aryl-C₁₋₃-alkyl, C₁₋₃-alkyl-carbonyl, C₁₋₄-alkyloxy-carbonyl, arylcarbonyl or aryl-C₁₋₃-alkyl-carbonyl groups, while the substituents may be identical or different, while the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 5. Compounds of general formula I according to claim 4, wherein R¹ denotes a methyl group, R² denotes an ethyl, propy, butyl or pentyl group, a phenyl group wherein two adjacent carbon atoms are linked together through a methylenedioxy or ethylenedioxy group, or a phenyl group and R³ denotes a C₁₋₄-alkyl group which may be terminally substituted by a C₁₋₄-alkoxy-carbonyl group, or a C₂₋₄-alkyl group which is terminally substituted by a C₁₋₃-alkyl-carbonylamino, phenylcarbonylamino, di-(C₁₋₃-alkyl)-amino, phenyl, pyridinyl or C₁₋₃-alkylsulphonylamino group, while the above-mentioned alkyl groups may be straight-chain or branched, the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 6. The following compounds of general formula I according to claim 1: (a) 5-acetyl-3-[3-(methoxycarbonylpropylamino)-(benzo-[1.3]dioxyo-5-yl)-methylidene]-2-indolinone

(b) 5-acetyl-3-[isopropylamino-phenyl-methylidene]-2-indolinone

(c) 5-acetyl-3-[propylamino-phenyl-methylidene]-2-indolinone

(d) 5-acetyl-3-[(3-methoxycarbonyl-propylamino)-(2.3-dihydro-benzo[1.4]dioxin-6-yl)-methylidene]-2-indolinone

(e) 5-acetyl-3-[(benzo[1.3]dioxol-5-yl)-(3-(benzoylamino-propylamino)-methylidene]-2-indolinone

(f) 5-acetyl-3-[(benzo[1.3]dioxol-5-yl)-(3-(butyrylamino-propylamino)-methylidene]-2-indolinone

(g) 5-acetyl-3-[(3-methanesulphonylamino-propylamino)-phenyl-methylidene]-2-indolinone

(h) 5-acetyl-3-[1-(3.4-difluorophenyl)-1-(N′,N′-dimethylhydrazino)-methylidene]-2-indolinone

(i) 5-acetyl-3-[1-(4-dimethylamino-butyl)-butenylidene]-2-indolinone

(j) 5-acetyl-3-[1-phenyl-1-(3-pyridin-3-yl-propylamino)-methylidene]-2-indolinone

and the tautomers, enantiomers, diastereomers, the mixtures thereof and the salts thereof.
 7. Physiologically acceptable salts of the compounds according to claim 1 with inorganic or organic acids or bases.
 8. Pharmaceutical compositions containing a compound according to claim 1 or a physiologically acceptable salt thereof with inorganic or organic acids or bases optionally together with one or more inert carriers and/or diluents.
 9. Process for preparing a pharmaceutical composition according to claim 8, characterised in that said compound is incorporated in one or more inert carriers and/or diluents by a non-chemical method.
 10. A method if treating type I and type II diabetes mellitus, diabetes associated disorders such as diabetic neuropathy and degenerative neurological diseases such as Alzheimer's disease, stroke, neurotraumatic injuries and bipolar disorders, said method comprised of the steps of administering to a patient in need therof an effective amoun of a compound according to claim 1 or a pharmaceutically accapetable salt thereof.
 11. Process for preparing the compounds of general formula I according to claims 1 comprised of the steps of: a) reacting a compound of general formula

wherein R¹ and R² are defined as in claim 1, R¹⁸ denotes a hydrogen atom or a protective group for the nitrogen atom of the lactam group and Z denotes a leaving group such as for example a halogen atom, a hydroxy, alkoxy, alkylsulphonyl, aralkylsulphonyl, or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy, methanesulphonyl, toluenesulphonyl or benzyloxy group, with an amine of general formula R³—NH₂  (III), wherein R³ is defined as in claim 1, while any hydroxy, amino or imino groups contained in the groups R² and/or R³ may temporarily be protected by suitable protective groups, said method further characterized in that: in order to prepare a compound of formula I which contains an aminocarbonyl group, a compound which contains a carboxy group is reacted with the corresponding amine, in order to prepare a compound of formula I which contains a carbonylamino group, a compound which contains an amino group is reacted with the corresponding acid chloride, in order to prepare a compound of formula I which contains an aminomethyl group, a compound which contains a cyano group is hydrogenated to form the corresponding aminomethyl derivative, in order to prepare a compound of formula I which contains an amino group, a compound which contains a nitro group is hydrogenated, and/or any protective groups which may be used during the reaction are then cleaved and/or the compounds of general formula I thus obtained are resolved into their enantiomers and/or diastereomers and/or the compounds of general formula I thus obtained are converted into their salts, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids or bases. 